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Lu P, Zhang F, Yang L, He Y, Kong X, Guo K, Xie Y, Xie H, Xie B, Jiang Y, Peng J. Bromodomain-containing protein 4 knockdown promotes neuronal ferroptosis in a mouse model of subarachnoid hemorrhage. Neural Regen Res 2026; 21:715-729. [PMID: 39104173 DOI: 10.4103/nrr.nrr-d-24-00147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/15/2024] [Indexed: 08/07/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202602000-00041/figure1/v/2025-05-05T160104Z/r/image-tiff Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage. Neuronal ferroptosis in particular plays an important role in early brain injury. Bromodomain-containing protein 4, a member of the bromo and extraterminal domain family of proteins, participated in multiple cell death pathways, but the mechanisms by which it regulates ferroptosis remain unclear. The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro . Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons, and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo . In addition, ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage. Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis. Using cleavage under targets and tagmentation analysis, we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro . Furthermore, treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074, a Raf-1 inhibitor, exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway. Moreover, targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage. Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage, and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
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Affiliation(s)
- Peng Lu
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Fan Zhang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Lei Yang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Yijing He
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Xi Kong
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Institute of Brain Science, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Kecheng Guo
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Yuke Xie
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Huangfan Xie
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Institute of Brain Science, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Bingqing Xie
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Institute of Brain Science, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Institute of Brain Science, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
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Huang X, Zhang Y, Jiang Y, Li T, Yang S, Wang Y, Yu B, Zhou M, Zhang G, Zhao X, Sun J, Sun X. Contribution of ferroptosis and SLC7A11 to light-induced photoreceptor degeneration. Neural Regen Res 2026; 21:406-416. [PMID: 39104162 PMCID: PMC12094538 DOI: 10.4103/nrr.nrr-d-23-01741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 04/27/2024] [Accepted: 07/03/2024] [Indexed: 08/07/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202601000-00043/figure1/v/2025-06-09T151831Z/r/image-tiff Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss. Ferroptosis has been demonstrated to be associated with retinal degenerative diseases. However, the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored. Bioinformatics and biochemical analyses in this study revealed xC - , solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model. This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway, through which cystine depletion, iron ion accumulation, and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment. We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo . Conversely, solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H 2 O 2 -induced ferroptosis of 661W cells. These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.
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Affiliation(s)
- Xiaoxu Huang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Yumeng Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Yuxin Jiang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Tong Li
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Shiqi Yang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Yimin Wang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Bo Yu
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Minwen Zhou
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Guanran Zhang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Xiaohuan Zhao
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Junran Sun
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
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Wang Y, Han Y, Li J, Wang Z, Li K, Bai T, Wang L, Sun Y, Chen C, Yu M. Cell-specific ferroptosis targeting tumors while sparing immune cells. Biomaterials 2025; 323:123457. [PMID: 40460787 DOI: 10.1016/j.biomaterials.2025.123457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 05/06/2025] [Accepted: 05/30/2025] [Indexed: 06/11/2025]
Abstract
Ferroptosis serves as a pivotal mechanism in diverse clinical chemotherapeutics and physiological processes, profoundly impacting tumor metabolism and the tumor microenvironment. Recently, the immunosuppression induced by ferroptosis has raised major concerns regarding tumor recurrence upon ferroptosis-based antitumor therapies. However, due to the lack of cell specificity, the antitumor and immunosuppressive effects in ferroptosis are inherently intertwined. Herein, we address the conflicting challenges between immunosuppression and antitumor efficacy in ferroptosis-based therapy by enabling cell-specific ferroptosis, thereby targeting tumors while sparing immune cells. By employing a specially designed nanoagent, i.e., ferrous selenide half-shell-covered gold, we induce notable upregulation of glutathione peroxidase 4 (GPX4) and downregulation of prostaglandin E2, leading to an increase in CD4+ and CD8+ T cell populations and intense antitumor immune responses. Despite the elevated level of GPX4, significant tumor cell ferroptosis is achieved, which is further promoted by the agent's photothermal and photocatalytic effects. Consequently, long-term immunological memory is established, yielding a long-lasting and recurrence-free antitumor efficacy spanning at least 200 days post-treatment. This work unlocks an avenue to balance immunosuppression reversal with tumor inhibition in ferroptosis-based therapies, providing promising prospects for antitumor therapies facing immunological hurdles in the tumor microenvironment.
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Affiliation(s)
- Yuanlin Wang
- Sichuan Provincial People's Hospital, School of Materials and Energy, University of Electronic Science and Technology, Chengdu, 610000, China; State Key Laboratory of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Yaqian Han
- School of Instrumentation Science and Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Jingshi Li
- State Key Laboratory of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Zhaotong Wang
- School of Instrumentation Science and Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Kai Li
- State Key Laboratory of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Tiancheng Bai
- State Key Laboratory of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Lei Wang
- Sichuan Provincial People's Hospital, School of Materials and Energy, University of Electronic Science and Technology, Chengdu, 610000, China; State Key Laboratory of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China
| | - Ye Sun
- School of Instrumentation Science and Engineering, Harbin Institute of Technology, Harbin, 150001, China.
| | - Chunying Chen
- National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100190, China
| | - Miao Yu
- Sichuan Provincial People's Hospital, School of Materials and Energy, University of Electronic Science and Technology, Chengdu, 610000, China; State Key Laboratory of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China.
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Liu Y, Chen N, He H, Liu L, Sun S. Sodium butyrate alleviates DSS-induced inflammatory bowel disease by inhibiting ferroptosis and modulating ERK/STAT3 signaling and intestinal flora. Ann Med 2025; 57:2470958. [PMID: 40028886 PMCID: PMC11878173 DOI: 10.1080/07853890.2025.2470958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/14/2025] [Accepted: 02/06/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), can seriously impact patients' quality of life. Sodium butyrate (NaB), a product of dietary fiber fermentation, has been shown to alleviate IBD symptoms. Some studies have shown that it is related to ferroptosis. However, the precise mechanism linking NaB, IBD, and ferroptosis is not clear. OBJECTIVE This study aimed to demonstrate that NaB suppresses ferroptosis, thereby alleviating inflammatory bowel disease (IBD) through modulation of the extracellular regulated protein kinases/signal transducer and activator of transcription 3 (ERK/STAT3) signaling pathway and intestinal flora. METHODS An IBD model was established using 2.5% (w/v) dextran sulfate sodium (DSS). Mice were orally administered low-dose NaB, high-dose NaB , or 5-aminosalicylic acid (5-ASA). Ferroptosis-related molecules were measured using specific kits, and western blotting (WB) and real-time polymerase chain reaction (RT-qPCR) were used to determine the levels of the target molecules. RESULTS NaB alleviated symptoms in IBD mice, including reduced weight loss, prolonged colon length, reduced disease activity index (DAI), and reduced spleen index and mRNA expression of inflammatory factors. Additionally, NaB reduced the content of Fe2+ and myeloperoxidase (MPO) and increased the content of GSH and the activity of superoxide dismutase (SOD), which reflected NaB-inhibited ferroptosis. Moreover, western blotting showed that NaB enhanced STAT3 and ERK phosphorylation. In addition, NaB regulates the composition and functions of flora related to IBD. CONCLUSION NaB alleviates IBD by inhibiting ferroptosis and modulating ERK/STAT3 signaling and the intestinal flora.
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Affiliation(s)
- Yingyin Liu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Nachuan Chen
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Huaxing He
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Lulin Liu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Suxia Sun
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
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Tang S, Long X, Li F, Jiang S, Fu Y, Liu J. Identification of RUVBL2 as a novel biomarker to predict the prognosis and drug sensitivity in multiple myeloma based on ferroptosis genes. Hematology 2025; 30:2467499. [PMID: 39985176 DOI: 10.1080/16078454.2025.2467499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Multiple myeloma (MM) is a hematological malignancy with the proliferation of malignant plasma cells. Numerous studies have highlighted the critical role of ferroptosis in MM. However, how to use ferroptosis-related genes (FRGs) for prognostic prediction and treatment guidance in MM remains unknown. METHODS By analysis of GEO databases, the prognostic gene was identified and a therapeutic strategy for MM patients based on FRGs was explored. A total of 12 FRGs were identified, utilizing the STRING database and Cytoscape software, and the PPI networks were constructed to identify hub genes and further functional enrichment analyses. Based on the aforementioned data, this study analyzed the expression of RUVBL2 in MM patients by qRT-PCR and Western blotting. To validate the functional role of RUVBL2 in the MM cells, cellular experiments were ultimately conducted. RESULTS The analysis highlighted six hub genes, including TP53, MCM5, TLR4, RUVBL2, GCLM and ITGA6, and functional enrichment analyses indicating enrichment in DNA replication, regulation of apoptotic signaling pathway and PI3K/AKT signaling pathway. Prognostic analysis indicated that TP53, RUVBL2, and MCM5 are associated with MM prognosis, with RUVBL2 displaying a notable area under the curve (AUC) of 0.823 in ROC analysis. The study first determined that RUVBL2 is highly expressed in MM, siRUVBL2-mediated deletion of RUVBL2 inhibited proliferation, promoted apoptosis and increased the sensitivity of BTZ in MM cells, and also overcame BTZ resistance in CD138+ primary cells from MM patients. CONCLUSIONS Our study first suggested that RUVBL2 may be regarded as potential therapeutic targets and prognostic value in MM.
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Affiliation(s)
- Sishi Tang
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Xinyi Long
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Fangfang Li
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Siyi Jiang
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Yunfeng Fu
- Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Jing Liu
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, People's Republic of China
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Hou Y, Fu Z, Wang C, Kucharzewska P, Guo Y, Zhang S. 27-Hydroxycholesterol in cancer development and drug resistance. J Enzyme Inhib Med Chem 2025; 40:2507670. [PMID: 40401382 PMCID: PMC12100970 DOI: 10.1080/14756366.2025.2507670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 04/25/2025] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
27-Hydroxycholesterol (27HC), a cholesterol metabolite, functions both as a selective oestrogen receptor (ER) modulator and a ligand for liver X receptors (LXRs). The discovery of 27HC involvement in carcinogenesis has unveiled new research avenues, yet its precise role remains controversial and context-dependent. In this review, we provide an overview of the biosynthesis and metabolism of 27HC and explore its cancer-associated signalling, with a particular focus on ER- and LXR-mediated pathways. Given the tissue-specific dual role of 27HC, we discuss its differential impact across various cancer types. Furthermore, we sort out 27HC-contributed drug resistance mechanisms from the perspectives of drug efflux, cellular proliferation, apoptosis, epithelial-mesenchymal transition (EMT), antioxidant defence, epigenetic modification, and metabolic reprogramming. Finally, we highlight the chemical inhibitors to mitigate 27HC-driven cancer progression and drug resistance. This review offers an updated role of 27HC in cancer biology, setting the stage for future research and the development of targeted therapeutics.
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Affiliation(s)
- Yaxin Hou
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, People’s Liberation Army of China (PLA), Beijing, China
| | - Chenhui Wang
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Paulina Kucharzewska
- Center of Cellular Immunotherapies, Warsaw University of Life Sciences, Warsaw, Poland
| | - Yuan Guo
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
| | - Sihe Zhang
- Department of Cell Biology, School of Medicine, Nankai University, Tianjin, China
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Miao M, Chen Y, Wang X, Li S, Hu R. The critical role of ferroptosis in virus-associated hematologic malignancies and its potential value in antiviral-antitumor therapy. Virulence 2025; 16:2497908. [PMID: 40302035 PMCID: PMC12045570 DOI: 10.1080/21505594.2025.2497908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/06/2025] [Accepted: 04/21/2025] [Indexed: 05/01/2025] Open
Abstract
Epstein-Barr Virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-cell leukemia virus type 1 (HTLV-1) are key infectious agents linked to the development of various hematological malignancies, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, and adult T-cell leukemia/lymphoma. This review highlights the critical knowledge gaps in understanding the role of ferroptosis, a novel form of cell death, in virus-related tumors. We focus on how ferroptosis influences the host cell response to these viral infections, revealing groundbreaking mechanisms by which the three viruses differentially regulate core pathways of ferroptosis, such as iron homeostasis, lipid peroxidation, and antioxidant systems, thereby promoting malignant transformation of host cells. Additionally, we explore the potential of antiviral drugs and ferroptosis modulators in the treatment of virus-associated hematological malignancies.
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Affiliation(s)
- Miao Miao
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuelei Chen
- College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, Liaoning, China
| | - Xuehan Wang
- Shenyang Shenhua Institute Test Technology, Shenyang, Liaoning, China
| | - Shengyang Li
- Publishing Department, Shenyang Agricultural University, Shenyang, Liaoning, China
| | - Rong Hu
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Zhang L, Liu X, Wang J, Li Z, Wang S, Yang W, Hai Y, Liu D. Kaempferol protects against doxorubicin-induced myocardial damage by inhibiting mitochondrial ROS-dependent ferroptosis. Redox Rep 2025; 30:2503130. [PMID: 40361284 PMCID: PMC12082743 DOI: 10.1080/13510002.2025.2503130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Doxorubicin (DOX), a widely used chemotherapeutic agent, is limited in clinical application due to its dose-dependent cardiotoxicity. Therefore, it is crucial to explore alternative therapeutic molecules or drugs for mitigating DOX-induced cardiomyopathy (DIC). In this study aimed to explore underlying mechanisms of the cardioprotective effects of Kaempferol (KP) against DIC. METHODS H9c2 cell-based DIC model were established to explore the pharmacological mechanism. The levels of mitochondrial membrane potential, mitochondrial ROS, mitochondrial Fe2+ and lipid peroxidation were detected using JC-1, TMRE, Mito-SOX, Mito-Ferro Green and C11-BODIPY 581/591 probes. Furthermore, Western blot analysis measured the expression of key regulatory proteins, and NRF2-targeting siRNA was transfected into H9c2 cells. The nuclear translocation of NRF2 was assessed by immunofluorescence. RESULTS Data revealed that KP mitigated DOX-induced mitochondrial damage and ferroptosis via reducing membrane potential, mitochondrial ROS/Fe²+, and regulating lipid metabolism. Mechanistically, Western blot analysis revealed that KP inhibited DOX-induced ferroptosis by activating NRF2/SLC7A11/GPX4 axis. Moreover, KP promoted the accumulation and nuclear translocation of NRF2 protein. CONCLUSION These findings demonstrated that KP protected against DOX-induced myocardial damage by inhibiting mitochondrial ROS-dependent ferroptosis. This provides novel insights into KP as a promising drug candidate for cardioprotection.
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Affiliation(s)
- Lin Zhang
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Xiaorui Liu
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Juan Wang
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Zimu Li
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Siqi Wang
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Wen Yang
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Yang Hai
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
- Key Laboratory of Dunhuang Medicine, Ministry of Education, Lanzhou, People’s Republic of China
| | - Dongling Liu
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
- Gansu Pharmaceutical Industry Innovation Research Institute, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
- Northwest Collaborative Innovation Center for Traditional Chinese Medicine, Lanzhou, People’s Republic of China
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Chen L, Wu Y, Lv T, Tuo R, Xiao Y. Mesenchymal stem cells enchanced by salidroside to inhibit ferroptosis and improve premature ovarian insufficiency via Keap1/Nrf2/GPX4 signaling. Redox Rep 2025; 30:2455914. [PMID: 39874130 PMCID: PMC11776066 DOI: 10.1080/13510002.2025.2455914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Regenerative medicine researches have shown that mesenchymal stem cells (MSCs) may be an effective treatment method for premature ovarian insufficiency (POI). However, the efficacy of MSCs is still limited. PURPOSE This study aims to explain whether salidroside and MSCs combination is a therapeutic strategy to POI and to explore salidroside-enhanced MSCs inhibiting ferroptosis via Keap1/Nrf2/GPX4 signaling. METHODS The effect of salidroside and MSCs on ovarian granular cells (GCs) was analyzed. After treatment, hormone levels and -fertility of rats were measured. Lipid peroxidation levels, iron deposition and mitochondrial morphology were detected. The genes and proteins of Keap1/Nrf2/GPX4 signaling were examined. RESULTS Salidroside and MSCs were found to inhibit cell death of GCs by reducing peroxidation and intracellular ferrous. Salidroside promotes the proliferation of MSCs and supports cell survival in ovary. Salidroside combined with MSCs therapy restored ovarian function, which was better than MSCs monotherapy. Salidroside-enhanced MSCs to inhibit ferroptosis. The results showed activation of the Keap1/Nrf2/GPX4 signaling and an increase in anti-ferroptosis molecule. CONCLUSIONS Salidroside-enhanced MSCs as a ferroptosis inhibitor and provide new therapeutic strategies for POI. The possible mechanisms of MSCs were related to maintaining redox homeostasis via a Keap1/Nrf2/GPX4 signaling.
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Affiliation(s)
- Lixuan Chen
- Department of Hematology, Shenzhen Qianhai Shekou Pilot Free Trade Zone Hospital, Shenzhen, People’s Republic of China
| | - Yingnan Wu
- Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China
| | - Tiying Lv
- Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Rui Tuo
- Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Yang Xiao
- Department of Hematology, Shenzhen Qianhai Shekou Pilot Free Trade Zone Hospital, Shenzhen, People’s Republic of China
- Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
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10
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Chen J, Zhou Q, Su L, Ni L. Mitochondrial dysfunction: the hidden catalyst in chronic kidney disease progression. Ren Fail 2025; 47:2506812. [PMID: 40441691 PMCID: PMC12123951 DOI: 10.1080/0886022x.2025.2506812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Accepted: 05/10/2025] [Indexed: 06/02/2025] Open
Abstract
Chronic kidney disease (CKD) represents a global health epidemic, with approximately one-third of affected individuals ultimately necessitating renal replacement therapy or transplantation. The kidney, characterized by its exceptionally high energy demands, exhibits significant sensitivity to alterations in energy supply and mitochondrial function. In CKD, a compromised capacity for mitochondrial ATP synthesis has been documented. As research advances, the multifaceted roles of mitochondria, extending beyond their traditional functions in oxygen sensing and energy production, are increasingly acknowledged. Empirical studies have demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of fibrosis and cellular apoptosis in CKD. Targeting mitochondrial dysfunction holds substantial therapeutic promise, with emerging insights into its epigenetic regulation in CKD, particularly involving non-coding RNAs and DNA methylation. This article presents a comprehensive review of contemporary research on mitochondrial dysfunction in relation to the onset and progression of CKD. It elucidates the associated molecular mechanisms across various renal cell types and proposes novel research avenues for CKD treatment.
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Affiliation(s)
- Jinhu Chen
- Department of Nephrology, Huanggang Central Hospital of Yangtze University, Huanggang, China
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiuyuan Zhou
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Pathology, Liang Ping People’s Hospital of Chongqing, Chongqing, People’s Republic of China
| | - Lianjiu Su
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
- Department of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Lihua Ni
- Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, China
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11
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Lv X, Yang C, Li X, Liu Y, Yang Y, Jin T, Chen Z, Jia J, Wang M, Li L. Ferroptosis and hearing loss: from molecular mechanisms to therapeutic interventions. J Enzyme Inhib Med Chem 2025; 40:2468853. [PMID: 39992186 PMCID: PMC11852237 DOI: 10.1080/14756366.2025.2468853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 02/25/2025] Open
Abstract
Hearing loss profoundly affects social engagement, mental health, cognition, and brain development, with sensorineural hearing loss (SNHL) being a major concern. Linked to ototoxic medications, ageing, and noise exposure, SNHL presents significant treatment challenges, highlighting the need for effective prevention and regeneration strategies. Ferroptosis, a distinct form of cell death featuring iron-dependent lipid peroxidation, has garnered interest due to its potential role in cancer, ageing, and neuronal degeneration, especially hearing loss. The emerging role of ferroptosis as a crucial mediator in SNHL suggests that it may offer a novel therapeutic target for otoprotection. This review aims to summarise the intricate connection between ferroptosis and SNHL, offering a fresh perspective for exploring targeted therapeutic strategies that could potentially mitigate cochlear cells damage and enhance the quality of life for individuals with hearing impairments.
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Affiliation(s)
- Xingyi Lv
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Chenyi Yang
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Xianying Li
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Yun Liu
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Yu Yang
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Tongyan Jin
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Zhijian Chen
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Jinjing Jia
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Min Wang
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
| | - Li Li
- Department of Physiology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, China
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12
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Xiao Y, He M, Zhang X, Yang M, Yuan Z, Yao S, Qin Y. Research progress on the mechanism of tumor cell ferroptosis regulation by epigenetics. Epigenetics 2025; 20:2500949. [PMID: 40327848 PMCID: PMC12064064 DOI: 10.1080/15592294.2025.2500949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/08/2025] Open
Abstract
Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.
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Affiliation(s)
- Yuyang Xiao
- Department of Health Management Medical, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Mengyang He
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Xupeng Zhang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Meng Yang
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Zhangchi Yuan
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Shanhu Yao
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Key Laboratory of Medical Information Research, Central South University, Changsha, Hunan, China
| | - Yuexiang Qin
- Department of Health Management Medical, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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13
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Kato K, Yasui H, Sato-Akaba H, Emoto MC, Fujii HG, Kmiec MM, Kuppusamy P, Nagane M, Yamashita T, Inanami O. Non-invasive electron paramagnetic resonance imaging detects tumor redox imbalance induced by ferroptosis. Redox Rep 2025; 30:2454887. [PMID: 39836064 PMCID: PMC11753017 DOI: 10.1080/13510002.2025.2454887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025] Open
Abstract
Targeting ferroptosis, cell death caused by the iron-dependent accumulation of lipid peroxides, and disruption of the redox balance are promising strategies in cancer therapy owing to the physiological characteristics of cancer cells. However, the detection of ferroptosis using in vivo imaging remains challenging. We previously reported that redox maps showing the reduction power per unit time of implanted tumor tissues via non-invasive redox imaging using a novel, compact, and portable electron paramagnetic resonance imaging (EPRI) device could be compared with tumor tissue sections. This study aimed to apply the EPRI technique to the in vivo detection of ferroptosis. Notably, redox maps reflecting changes in the redox status of tumors induced by the ferroptosis-inducing agent imidazole ketone erastin (IKE) were compared with the immunohistochemical images of 4-hydroxynonenal (4-HNE) in tumor tissue sections. Our comparison revealed a negative correlation between the reducing power of tumor tissue and the number of 4-HNE-positive cells. Furthermore, the control and IKE-treated groups exhibited significantly different distributions on the correlation map. Therefore, redox imaging using EPRI may contribute to the non-invasive detection of ferroptosis in vivo.
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Affiliation(s)
- Kazuhiro Kato
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Hironobu Yasui
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- One Health Research Center, Hokkaido University, Sapporo, Japan
| | - Hideo Sato-Akaba
- Department of Electrical and Electronic Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, Hamamatsu, Japan
| | - Miho C. Emoto
- Department of Clinical Laboratory Science, School of Medical Technology, Health Sciences University of Hokkaido, Sapporo, Japan
| | - Hirotada G. Fujii
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Ishikari, Japan
| | - Maciej M. Kmiec
- Departments of Radiology and Radiation Oncology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Periannan Kuppusamy
- Departments of Radiology and Radiation Oncology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Masaki Nagane
- Laboratory of Biochemistry, School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Tadashi Yamashita
- Laboratory of Biochemistry, School of Veterinary Medicine, Azabu University, Sagamihara, Japan
| | - Osamu Inanami
- Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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14
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Gao Q, Zhou Y, Chen Y, Hu W, Jin W, Zhou C, Yuan H, Li J, Lin Z, Lin W. Role of iron in brain development, aging, and neurodegenerative diseases. Ann Med 2025; 57:2472871. [PMID: 40038870 PMCID: PMC11884104 DOI: 10.1080/07853890.2025.2472871] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within the central nervous system, including oxygen transport, energy metabolism, and the synthesis and catabolism of myelin and neurotransmitters. During brain development, iron is distributed throughout the brain, playing a pivotal role in key processes such as neuronal development, myelination, and neurotransmitter synthesis. In physiological aging, iron can selectively accumulate in specific brain regions, impacting cognitive function and leading to intracellular redox imbalance, mitochondrial dysfunction, and lipid peroxidation, thereby accelerating aging and associated pathologies. Furthermore, brain iron accumulation may be a primary contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Comprehending the role of iron in brain development, aging, and neurodegenerative diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction of abnormal neurological states, and implementing appropriate interventions may be instrumental in preserving normal central nervous system function.
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Affiliation(s)
- Qiqi Gao
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiyang Zhou
- Department of Urology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Yu Chen
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Hu
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenwen Jin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chunting Zhou
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hao Yuan
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianshun Li
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhenlang Lin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Lin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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15
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Deng S, Cao H, Li T, Wang X, Meng J, Zeng T, Zhang D, Zhang S, Wang G, Liu R, Zou T, Cai M, Lang R, Lu D, Gu J. Lachnospiraceae-bacterium alleviates ischemia-reperfusion injury in steatotic donor liver by inhibiting ferroptosis via the Foxo3-Alox15 signaling pathway. Gut Microbes 2025; 17:2460543. [PMID: 39882747 PMCID: PMC11784649 DOI: 10.1080/19490976.2025.2460543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 01/31/2025] Open
Abstract
Ischemia-reperfusion injury (IRI) is a major obstacle in liver transplantation, especially with steatotic donor livers. Dysbiosis of the gut microbiota has been implicated in modulating IRI, and Lachnospiraceae plays a pivotal role in regulating host inflammatory and immune responses, but its specific role in liver transplantation IRI remains unclear. This study explores whether Lachnospiraceae can mitigate IRI and its underlying mechanisms. We found Lachnospiraceae-bacterium (Lachn.) abundance was significantly reduced in rats with liver cirrhosis. Lachn.-treated rats exhibited improved intestinal permeability, reduced IRI severity in both normal and steatotic donor livers, and decreased levels of neutrophil and macrophage infiltration, and inflammatory cytokines. Multi-omics analysis revealed elevated pyruvate levels in transplanted livers after Lachn. treatment, alongside reduced Alox15 and Foxo3 expression. Mechanistically, Lachn.-derived pyruvate inhibited Alox15 expression and reduced ferroptosis in normal and steatotic donor livers. Furthermore, reduced nuclear translocation of Foxo3 further suppressed Alox15 expression, alleviating IRI, especially in steatotic donor livers. Clinical samples confirmed reduced donor livers IRI in cirrhotic recipients with high Lachn. abundance after liver transplantation. In conclusion, Lachn. alleviates IRI in steatotic donor liver transplantation by inhibiting ferroptosis via the Foxo3-Alox15 axis, providing a potential therapeutic strategy to modulate gut microbiota to alleviate IRI following liver transplantation.
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Affiliation(s)
- Shenghe Deng
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huan Cao
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tongxi Li
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xueling Wang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Junpeng Meng
- Department of General Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Teng Zeng
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Di Zhang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shuhua Zhang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Guoliang Wang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ran Liu
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tianhao Zou
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mao Cai
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jinyang Gu
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China
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16
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Ren X, Zhao L, Hao Y, Huang X, Lv G, Zhou X. Copper-instigated modulatory cell mortality mechanisms and progress in kidney diseases. Ren Fail 2025; 47:2431142. [PMID: 39805816 PMCID: PMC11734396 DOI: 10.1080/0886022x.2024.2431142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/23/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025] Open
Abstract
Copper is a vital cofactor in various enzymes, plays a pivotal role in maintaining cell homeostasis. When copper metabolism is disordered and mitochondrial dysfunction is impaired, programmed cell death such as apoptosis, paraptosis, pyroptosis, ferroptosis, cuproptosis, autophagy and necroptosis can be induced. In this review, we focus on the metabolic mechanisms of copper. In addition, we discuss the mechanism by which copper induces various programmed cell deaths. Finally, this review examines copper's involvement in prevalent kidney diseases such as acute kidney injury and chronic kidney disease. The findings indicate that the use of copper chelators or plant extracts can mitigate kidney damage by reducing copper accumulation, offering novel insights into the pathogenesis and treatment strategies for kidney diseases.
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Affiliation(s)
- Xiya Ren
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Limei Zhao
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yajie Hao
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiu Huang
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guangna Lv
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoshuang Zhou
- Department of Nephrology, Shanxi Provincial People’s Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
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17
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Lyu G, Liao H, Li R. Ferroptosis and renal fibrosis: mechanistic insights and emerging therapeutic targets. Ren Fail 2025; 47:2498629. [PMID: 40329437 PMCID: PMC12057793 DOI: 10.1080/0886022x.2025.2498629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 04/01/2025] [Accepted: 04/13/2025] [Indexed: 05/08/2025] Open
Abstract
Ferroptosis is a regulated, iron-dependent form of cell death driven by lipid peroxidation and distinct from apoptosis, necroptosis, and pyroptosis. Recent studies implicate ferroptosis as a central contributor to the pathogenesis of renal fibrosis, a hallmark of chronic kidney disease associated with high morbidity and progression to end-stage renal failure. This review synthesizes current evidence linking ferroptotic signaling to fibrotic remodeling in the kidney, focusing on iron metabolism dysregulation, glutathione peroxidase 4 (GPX4) inactivation, lipid peroxide accumulation, and ferroptosis-regulatory pathways such as FSP1-CoQ10-NAD(P)H and GCH1-BH4. We detail how ferroptosis in tubular epithelial cells modulates pro-fibrotic cytokine release, macrophage recruitment, and TGF-β1-driven extracellular matrix deposition. Moreover, we explore ferroptosis as a therapeutic vulnerability in renal fibrosis, highlighting promising agents including iron chelators, GPX4 activators, anti-lipid peroxidants, and exosome-based gene delivery systems. By consolidating emerging preclinical data, this review provides a comprehensive mechanistic framework and identifies translational opportunities for targeting ferroptosis in fibrotic kidney disease.
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Affiliation(s)
- Guangna Lyu
- The Nephrology Department of Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan, China
- The Second People’s Hospital of Shanxi Province, Taiyuan, China
| | - Hui Liao
- The Drug Clinical Trial Institution of Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan, China
| | - Rongshan Li
- The Nephrology Department of Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan, China
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18
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Zuo CJ, Tian J. Advancing the understanding of the role of apoptosis in lung cancer immunotherapy: Global research trends, key themes, and emerging frontiers. Hum Vaccin Immunother 2025; 21:2488074. [PMID: 40186454 PMCID: PMC11980473 DOI: 10.1080/21645515.2025.2488074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/12/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025] Open
Abstract
Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.
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Affiliation(s)
- Chun-Jian Zuo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tian
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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19
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Lin Y, Pu Y, Wang X, Zhang Q, Tang H, Jin B, Cao M, Feng Y, Chen X, Zhu X, Zhou H. High resolution two photon fluorescence probe monitoring ClO - based on anion exchange for the synergistic ROS and ferroptosis activated by thermal energy. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 339:126277. [PMID: 40279880 DOI: 10.1016/j.saa.2025.126277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 04/11/2025] [Accepted: 04/19/2025] [Indexed: 04/29/2025]
Abstract
Ferroptosis, closely correlated with hypochlorite (ClO-), is an emerging form of iron-dependent cell death. Exploring the ClO- content in living cells will help to further reveal the biological function of ferroptosis. In this work, we have developed a two-photon excited fluorescent probe (CMI-ClO) which can detect the ClO- changes during ferroptosis. CMI-ClO can specifically response to ClO- by exchanging with I-. The multiple reactive oxygen species (ROS) are produced simultaneously in the ClO- identification process. More significantly, CMI-ClO produces ROS through thermal energy, breaking the limitation of light trigged conventional photosensitizers. CMI-ClO can achieve high resolution tracking of ferroptosis under NIR II excitation, where ROS and ferroptosis combine to cause mitochondrial damage and cell death. This work provides a synergistic strategy for enhancing ROS and ferroptosis therapy.
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Affiliation(s)
- Yitong Lin
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Yan Pu
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Xingchen Wang
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Qiong Zhang
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China.
| | - Haifeng Tang
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Baocheng Jin
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Ming Cao
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China.
| | - Yan Feng
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Xingxing Chen
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Xiaojiao Zhu
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China
| | - Hongping Zhou
- School of Chemistry and Chemical Engineering, Center of Free Electron Laser & High Magnetic Field, Key Laboratory of Structure and Functional Regulation of Hybrid Materials Ministry of Education, Key Laboratory of Functional Inorganic Materials Chemistry of Anhui Province, and Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials of Anhui Province, Anhui University, PR China; School of Chemical and Environmental Engineering, Anhui Polytechnic University, 241000 Wuhu, PR China.
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20
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Zheng Q, Wang D, Lin R, Xu W. Pyroptosis, ferroptosis, and autophagy in spinal cord injury: regulatory mechanisms and therapeutic targets. Neural Regen Res 2025; 20:2787-2806. [PMID: 39101602 PMCID: PMC11826477 DOI: 10.4103/nrr.nrr-d-24-00112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/24/2024] [Accepted: 06/07/2024] [Indexed: 08/06/2024] Open
Abstract
Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
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Affiliation(s)
- Qingcong Zheng
- Department of Spinal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Du Wang
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| | - Rongjie Lin
- Department of Orthopedic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Weihong Xu
- Department of Spinal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
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21
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Liu W, Xie X, Zong H, Li Y, Ding Y, Liu Z, Wan B, Xiao T, Lv F, Tang C, Yu L, Wang P, Lai Z. Design, synthesis and biological evaluation of triazolothiadiazole derivatives as FSP1 inhibitors for sensitizing cancer cells to ferroptosis. Eur J Med Chem 2025; 293:117737. [PMID: 40378717 DOI: 10.1016/j.ejmech.2025.117737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/26/2025] [Accepted: 05/07/2025] [Indexed: 05/19/2025]
Abstract
Ferroptosis suppressor protein 1 (FSP1) is a recently identified ferroptosis suppressor that functions independently of the glutathione peroxidase reductase 4 (GPX4)-mediated pathway. Mechanistically, FSP1 mitigates ferroptosis by catalyzing the reduction of ubiquinone to ubiquinol and vitamin K (VK) to hydroquinone, thereby reducing lethal lipid peroxidation through the neutralization of free radicals. In this study, we designed and synthesized 32 compounds to systematically explore their structure-activity relationship (SAR) with the aim of identifying potent and novel FSP1 inhibitors. Among these, compound 39, a triazolothiadiazole derivative, exhibited the most significant inhibitory activity against FSP1, with an IC50 value of 35 nM. In vitro cellular assays demonstrated that compound 39 markedly enhanced RSL3-induced lipid peroxide (LPO) accumulation and sensitized cancer cells from diverse tissue origins to RSL3-induced ferroptosis. Furthermore, by exploiting the FSP1-mediated reduction of VK, compound 39 effectively augmented ferroptosis in HT1080 cells pretreated with RSL3 and VK through its potent inhibition of FSP1 activity. To the best of our knowledge, this study represents the first pharmacochemical investigation dedicated to the systematic design and synthesis of FSP1 inhibitors. Collectively, our findings underscore the profound impact of compound 39 on tumor ferroptosis, providing a promising foundation for the development of FSP1 inhibitors as potential therapeutic agents in cancer treatment.
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Affiliation(s)
- Wenbin Liu
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Xiaoying Xie
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Haonan Zong
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Yaxu Li
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yan Ding
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Zhe Liu
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Bingrui Wan
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Ting Xiao
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Feng Lv
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Chunlei Tang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China
| | - Lei Yu
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
| | - Ping Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
| | - Zengwei Lai
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China.
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22
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Geng H, Zhou L, Zhang P, Li X, Guo Y, Cui H, Chen X. WTAP targets SOX2 to inhibit trophoblast ferroptosis in the pathogenesis of preeclampsia via m6A-dependent ferroptosis regulation. Cell Signal 2025; 133:111881. [PMID: 40383175 DOI: 10.1016/j.cellsig.2025.111881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/08/2025] [Accepted: 05/15/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Preeclampsia (PE) is associated with trophoblast damage, which may be caused by aberrant ferroptosis, an important process in placental development and function. The key component of N6-methyladenosine (m6A)-wilms tumor 1 associated protein (WTAP) has been reported to be involved in the migration and invasion of trophoblasts in the pathogenesis of PE. However, the connection between WTAP and ferroptosis in PE remained poorly understood. Accordingly, in order to explore potential treatments for PE, and understand how WTAP influences the trophoblasts' ferroptosis in PE, researchers conducted in vitro and in vivo experiments. METHODS Relevant molecular biology assays were conducted to investigate the effect of WTAP. RESULTS Here, we report that both m6A and WTAP levels were downregulated in placental tissue samples of 20 PE participants and the hypoxia model of trophoblast cell line HTR-8/SVneo, and down-regulation of WTAP promotes PE progression through m6A-dependent ferroptosis regulation. Stem cell transcriptional factor (SOX2) can specifically bind to the promoters of ferroptosis-related genes GPX4, SLC7A11, and FTH1 to regulate their expression in HTR-8/SVneo cells. In terms of molecular mechanisms, WTAP in trophoblast targeted the SOX2 gene. Through binding to its 3'-UTR m6A site, WTAP increased the stability of SOX2 mRNA. Moreover, animal studies demonstrated that WTAP could suppress ferroptosis and alleviate the symptoms of preeclampsia in the rat model of preeclampsia via SOX2. CONCLUSION WTAP mediates the m6A modification of SOX2 to regulate trophoblast ferroptosis in vitro and in vivo. Our findings point to a novel approach to treating PE and provide the groundwork for future research into this disease's RNA epigenetic regulation mechanisms.
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Affiliation(s)
- Hao Geng
- School of Medicine, Nankai University, Tianjin 300071, China; Department of Obstetrics, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin 300100, China
| | - Limei Zhou
- Department of Gynecology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China
| | - Pei Zhang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Xing Li
- Department of Obstetrics, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China
| | - Ying Guo
- Department of Obstetrics, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China
| | - Hongyan Cui
- Department of Obstetrics, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China
| | - Xu Chen
- School of Medicine, Nankai University, Tianjin 300071, China; Department of Obstetrics, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin 300100, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin 300100, China.
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23
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Li YY, Peng YQ, Yang YX, Xu N, Shi TJ, Liu RX, Luan YY, Yin CH. Fundamental mechanisms of cell death for polycystic ovary syndrome. Biochem Biophys Rep 2025; 43:102043. [PMID: 40519700 PMCID: PMC12167107 DOI: 10.1016/j.bbrep.2025.102043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 04/16/2025] [Accepted: 05/06/2025] [Indexed: 06/18/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of childbearing age with complex symptoms and multiple hormone imbalances. Patients usually present with irregular menstruation, ovarian cysts, and metabolic abnormalities. Current research has been found that multiple cell death programs may be involved in the occurrence of the disease. This article focuses on the mechanism between PCOS and six cell death processes including apoptosis, autophagy, ferroptosis, pyroptosis, NETosis and necroptosis. Ovarian granulosa cell apoptosis, autophagy, and ferroptosis play key roles in PCOS. In addition, pyroptosis and NETosis may also be involved, but the specific mechanism needs further study. In general, a deeper understanding of these cell death mechanisms will help develop innovative treatments for PCOS.
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Affiliation(s)
- Ying-ying Li
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Yi-qiu Peng
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Yu-xi Yang
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Ning Xu
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Ting-juan Shi
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Rui-xia Liu
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Ying-yi Luan
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Cheng-hong Yin
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
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24
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Shi X, Xu W, Xue Y, Zhao D, Lv H, Han D, Mao Y, Du Z. Dioscin improves hypertrophic scars by inducing apoptosis and ferroptosis of scar fibroblasts through mitochondrial oxidative stress damage. Eur J Pharmacol 2025; 1001:177759. [PMID: 40412745 DOI: 10.1016/j.ejphar.2025.177759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 05/16/2025] [Accepted: 05/21/2025] [Indexed: 05/27/2025]
Abstract
Hypertrophic scar (HS) is a common fibrotic disease primarily caused by excessive activation and proliferation of fibroblasts. Dioscin, a steroidal saponin isolated from the roots of Dioscorea plants, has been shown to be effective in the management of metabolic disorders, regulation of inflammation, and inhibition of tumor growth. This study investigates the inhibitory effects of Dioscin on the proliferation and functionality of human scar fibroblasts (HSFs) and its therapeutic potential for HS, as well as the underlying mechanisms involved. The impact of Dioscin on collagen secretion and HSFs activation was assessed using Reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). HSFs functionality was evaluated through EdU proliferation, wound healing, transwell migration, and contracture assays. RNA sequencing revealed that Dioscin triggers HSFs apoptosis and ferroptosis by compromising mitochondrial membrane potential. Immunofluorescence and WB were employed to examine the mechanisms of Dioscin-induced apoptosis and ferroptosis. The therapeutic efficacy of Dioscin was further assessed in vivo using a rabbit ear scar model. Results show that Dioscin suppresses HSFs proliferation, migration, and contraction, reduces collagen secretion, and deactivates HSFs by destabilizing mitochondrial membrane potential, leading to ROS accumulation. Local administration of Dioscin significantly mitigates scar formation in rabbit ears. In conclusion, Dioscin reduces HS progression by disrupting mitochondrial membrane potential, inducing oxidative stress, and promoting apoptosis and ferroptosis in HSFs, highlighting its potential as a therapeutic agent for HS.
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Affiliation(s)
- Xiaofeng Shi
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China
| | - Wei Xu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China
| | - Yaxin Xue
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China
| | - Danyang Zhao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China
| | - Hao Lv
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China
| | - Dong Han
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China.
| | - Yuanqing Mao
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China.
| | - Zijing Du
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, 200011, Shanghai, China.
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25
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Wang X, Liu Z, Lin C. Metal ions-induced programmed cell death: how does oxidative stress regulate cell death? Life Sci 2025; 374:123688. [PMID: 40328371 DOI: 10.1016/j.lfs.2025.123688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 04/20/2025] [Accepted: 05/01/2025] [Indexed: 05/08/2025]
Abstract
In recent years, the mechanisms of ferroptosis and cuproptosis, two novel modes of cell death, have been elucidated and have attracted much attention. Ferroptosis is dependent on the metabolic disruption of iron ions and lipid peroxidation, whereas cuproptosis is closely related to intracellular accumulation of copper ions, aggregation of lipoylated proteins and damage to FeS cluster proteins. In particular, oxidative stress plays an important role in both types of cell death. During ferroptosis, the central role of oxidative stress is reflected in the overproduction of reactive oxygen species (ROS) and lipid peroxidation of the cell membrane. Recent studies have revealed that ROS can propagate over long distances across cells in the form of trigger waves, triggering large-scale ferroptosis. In embryonic development, different regional redox states can limit the long-distance propagation of ferroptosis waves, which is critical for muscle remodeling and tissue formation during development. In cuproptosis, processes such as copper ions accumulation, tricarboxylic acid (TCA) cycle blockade, and reduced level of FeS cluster proteins are closely associated with oxidative stress. In addition, there is a close link between oxidative stress and death induced by other metal ions (Ca2+, Zn2+, etc.). In this paper, we review the role of oxidative stress in ferroptosis and cuproptosis and the related research progress to provide new ideas for understanding the mechanism of cell death and the occurrence and treatment of related diseases.
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Affiliation(s)
- Xingsheng Wang
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
| | - Zuohao Liu
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China
| | - Changjun Lin
- School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
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26
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Zhou P, Liu M, Lv T. Ferroptosis targeting offers a therapeutic target for septic cardiomyopathy. Tissue Cell 2025; 95:102930. [PMID: 40288080 DOI: 10.1016/j.tice.2025.102930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/05/2025] [Accepted: 04/22/2025] [Indexed: 04/29/2025]
Abstract
Sepsis-induced cardiac dysfunction, usually termed sepsis-induced cardiomyopathy or septic cardiomyopathy(SCM), is developed in approximately 70 % of the patients with sepsis, making it is a major concern for sepsis patients. However, the pathogenesis of SCM remain incompletely understood. Ferroptosis, a newly identified mechanism of regulated cell death, characterized by a decline in antioxidant capacity, iron accumulation, and lipid peroxidation(LPO), is involved in sepsis and SCM. Moreover, ferroptosis inhibitors confer a novel therapeutic regimen in SCM. In this Review, we first summarizes the core mechanism of ferroptosis, with an emphasis on how best to interpret ferroptosis leads to the genesis of SCM. We then highlights our focus on the emerging different types of therapeutic ferroptosis inhibitors and summarizes their pharmacological beneficial effect to treat SCM. This review highlights a novel potential therapeutic strategy for SCM by pharmacologically inhibiting ferroptosis.
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Affiliation(s)
- Pengsi Zhou
- Department of Cardiology, The Affiliated Hospital of Chifeng University, Chifeng 024005, China.
| | - Mengxue Liu
- Department of Cardiology, The Affiliated Hospital of Chifeng University, Chifeng 024005, China
| | - Tao Lv
- Department of Cardiology, The Affiliated Hospital of Chifeng University, Chifeng 024005, China.
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27
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Qiu L, Liu H, Chen S, Wu Y, Yan J. Ferroptosis contributed to endoplasmic reticulum stress in preterm birth by targeting LHX1 and IRE-1. Cell Signal 2025; 132:111777. [PMID: 40157471 DOI: 10.1016/j.cellsig.2025.111777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
Preterm birth (PTB) significantly contributed to neonatal mortality, emphasizing the need for a detailed understanding of its pathogenesis. This study aimed to explore the involvement of ferroptosis, an iron-dependent cell death process, in PTB and investigated the possible crosstalk with endoplasmic reticulum stress (ERS). First, we explored the occurrence of ferroptosis in placenta samples from PTB parturients. Then we established a ferroptosis cell model was established by subjecting trophoblast cells to hypoxia/reoxygenation (H/R), and found the ERS was induced in H/R exposed cells and was attenuated by ferroptosis inhibition using Fer-1, suggesting that ferroptosis could induce ERS. Meanwhile, we also induced ERS in trophoblast cells via tunicamycin (TM) treatment. Ferroptosis inhibition with Fer-1 alleviated TM-induced ER stress. TM treatment reduced trophoblast cell viability and migration while promoted apoptosis and autophagy, effects that were reversed by ferroptosis inhibition. Thus, targeting ferroptosis might help mitigate ER stress-related pathophysiological changes in PTB. Mechanically, we found two ERS mediators LIM homeobox 1 (LHX1)/Inositol-requiring enzyme 1 (IRE-1) were also upregulated in H/R treated cells. Silencing LHX1 or IRE-1 was demonstrated to reverse the H/R-induced ferroptosis. Additionally, rescue assays further revealed that LHX1 promoted ferroptosis by regulating IRE-1. In conclusion, ferroptosis contributed to ERS and was critically involved in PTB, highlighting the LHX1/IRE-1 axis as a promising therapeutic target for mitigating ferroptosis-related complications. These findings offered a foundation for innovative interventions in preterm birth.
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Affiliation(s)
- Liyin Qiu
- Department of Obstetrics, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian 350001, China
| | - Hui Liu
- Department of Histology and Embryology, Fujian Medical University, Fuzhou, Fujian 350001, China
| | - Shali Chen
- Department of Obstetrics, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian 350001, China
| | - Yiting Wu
- Department of Obstetrics, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian 350001, China
| | - Jianying Yan
- Department of Obstetrics, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian 350001, China.
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28
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Jian G, Wang S, Wang X, Lu Q, Zhu X, Wan S, Wang S, Li D, Wang C, He Q, Chen T, Song J. Enhanced sequential osteosarcoma therapy using a 3D-Printed bioceramic scaffold combined with 2D nanosheets via NIR-II photothermal-chemodynamic synergy. Bioact Mater 2025; 50:540-555. [PMID: 40391104 PMCID: PMC12088772 DOI: 10.1016/j.bioactmat.2025.04.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/03/2025] [Accepted: 04/22/2025] [Indexed: 05/21/2025] Open
Abstract
Background Osteosarcoma (OS) is a malignant tumor originating from primitive mesenchymal cells, characterized by rapid metastasis, high invasiveness, and significant mortality. The primary challenges in OS management include the effective elimination of residual tumor cells to prevent recurrence and the repair of extensive bone defects caused by surgical intervention. Objective This study aims to develop an innovative biomimetic 3D-printed bioactive glass ceramic (BGC) scaffold modified with two-dimensional nanosheets to address both tumor ablation and bone tissue repair. Materials and methods The nanosheets were constructed via ellagic acid (EA) and ruthenium (Ru) coordination, leveraging the non-topological adhesion properties of catechol in EA to deposit the nanosheets onto the BGC scaffold (EARu-BGC). The therapeutic effects of EARu-BGC were evaluated in vitro and in vivo. Results EARu-BGC sequentially responds to the local microenvironment during OS treatment. During the tumor ablation phase, EARu-BGC induced ferroptosis through the synergistic effects of photothermal and chemodynamic therapy, achieving over 90 % tumor cell ablation and significantly inhibiting tumor volume and weight. In the bone tissue repair phase, EARu-BGC exhibited adaptive ROS scavenging and facilitated a pro-healing microenvironment, promoting osteogenic differentiation. The gradual degradation of the BGC scaffold provided essential minerals and space for new bone formation. In vivo experiments demonstrated that EARu-BGC significantly enhanced osteogenesis, increasing the trabecular number to 1.51 ± 0.15/mm and reducing trabecular separation to 1.50 ± 0.04 mm. Conclusion The EARu-BGC scaffold presents a promising multifunctional platform for OS treatment by effectively balancing antitumor efficacy with bone repair capabilities.
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Affiliation(s)
- Guangyu Jian
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Si Wang
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Xinlu Wang
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Qinyi Lu
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Xingyu Zhu
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Shucheng Wan
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Shan Wang
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Dize Li
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Chao Wang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, School of Engineering Medicine, Beihang University, Beijing 100083, PR China
| | - Qingqing He
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Tao Chen
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
| | - Jinlin Song
- The Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key aboratory of Oral Biomedical Engineering of Higher Education, Chongqing Municipal Health Commission Key Laboratory of Oral Biomedical Engineering, Chongqing, 401147, PR China
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Song R, Yin S, Wu J, Yan J. Neuronal regulated cell death in aging-related neurodegenerative diseases: key pathways and therapeutic potentials. Neural Regen Res 2025; 20:2245-2263. [PMID: 39104166 PMCID: PMC11759035 DOI: 10.4103/nrr.nrr-d-24-00025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/13/2024] [Accepted: 06/18/2024] [Indexed: 08/07/2024] Open
Abstract
Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, and has been proven to be an important regulatory mechanism for regulating neuronal aging and death. However, excessive activation of regulated cell death may lead to the progression of aging-related diseases. This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases. Notably, the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases. These forms of cell death exacerbate disease progression by promoting inflammation, oxidative stress, and pathological protein aggregation. The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms, with a focus on ferroptosis, cuproptosis, and disulfidptosis. For instance, FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation, while copper mediates glutathione peroxidase 4 degradation, enhancing ferroptosis sensitivity. Additionally, inhibiting the Xc- transport system to prevent ferroptosis can increase disulfide formation and shift the NADP + /NADPH ratio, transitioning ferroptosis to disulfidptosis. These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms. In conclusion, identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.
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Affiliation(s)
- Run Song
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
| | - Shiyi Yin
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
| | - Jiannan Wu
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
| | - Junqiang Yan
- Department of Neurology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
- Neuromolecular Biology Laboratory, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan Province, China
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Burns GD, Schneider K, Atilano S, Chwa M, Chang S, Kenney MC, Singh MK. Dual effects of erastin on aggressive osteosarcoma cells: ferroptosis sensitization and anti-ferroptotic gene activation. Cytotechnology 2025; 77:128. [PMID: 40567388 PMCID: PMC12185812 DOI: 10.1007/s10616-025-00795-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 06/12/2025] [Indexed: 06/28/2025] Open
Abstract
Osteosarcoma (OS) is a rare cancer, yet the most prevalent primary bone cancer in adolescents and young adults OS can be fatal and detrimental due to its high aggressiveness, early metastases, and chemo-resistance. Recent research suggests that drugs that induce ferroptosis could treat osteosarcoma. It is unknown how erastin-induced ferroptosis influences differential gene expression of System Xc, iron absorption, heme synthesis, and mono- (MUFA) and polyunsaturated (PUFA) fatty acid levels in aggressive OS cells. In this study, we show that erastin-induced ferroptosis decreases OS cell growth and survival by raising total ROS, mitochondrial membrane potential, and downregulating VDAC2. Furthermore, erastin induces elevated levels of SLC7A11 and SLC3A2, but downregulation of TFRC and HMOX1 in OS cells. Notably, the addition of Ferrostatin-1 protects against Erastin-induced cytotoxicity, implying that these agents induce ferroptosis. We also showed that Ferrostatin-1 provides partial protection against Erastin-induced ferroptosis by stimulating the unique transcriptional gene profile of System Xc-, MUFA, and PUFA while inhibiting iron uptake and heme production in OS cells. These findings show that Erastin inhibits the survival of aggressive OS cells, but it also increases the expression of genes linked with anti-ferroptosis activity, which could lead to preventing ferroptosis in the aggressive OS phenotype. Targeting this anti-ferroptotic differential gene expression mediated by erastin-induced ferroptosis in OS cells may help to improve erastin's efficacy. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-025-00795-7.
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Affiliation(s)
- Gordon Daniel Burns
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
| | - Kevin Schneider
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
| | - Shari Atilano
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
| | - Marilyn Chwa
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
| | - Steven Chang
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
| | - M. Cristina Kenney
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92697 USA
| | - Mithalesh Kumar Singh
- Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697 USA
- Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX USA
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Guo C, Guo Y, Zhang J, Wang J, Su L, Ning X, Chen X, Yan H. Grx2 maintains GSH/GSSG homeostasis to enhance GPX4-mediated ferroptosis defense in UVB irradiation induced cataract. Exp Eye Res 2025; 257:110421. [PMID: 40368151 DOI: 10.1016/j.exer.2025.110421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/13/2025] [Accepted: 05/11/2025] [Indexed: 05/16/2025]
Abstract
PURPOSE Ultraviolet B (UVB) irradiation induces cataract pathogenesis, and Glutaredoxin 2 (Grx2) deficiency causes the early onset of UVB-induced cataracts. Several researchers have shown that, apart from apoptosis and pyroptosis, UVB irradiation also can induce cell ferroptosis. We explored the role of ferroptosis caused by UVB irradiation in human lens epithelial cells (HLECs) and clarified how Grx2 protects against UVB-induced cataracts. METHODS HLE-B3 cells and mice lenses were treated with DMSO or ferroptosis inhibitors after various doses of UVB irradiation. Cell morphology and ultrastructure were observed by optical microscope and transmission electron microscopy. Lens opacity was observed ex vivo using an optical microscope and in vivo using a slit lamp. The lipid peroxidation level was measured by C11-BODIPY probe and 4-HNE (the lipid peroxidation marker) protein expression. Cell viability was determined using the CCK-8 kit and propodium iodide (PI) immunofluorescence. Grx2 KO and KI mice, Grx2 silencing and Grx2 overexpression in HLE-B3 cell lines were used for in vivo and in vitro experiments respectively. RESULTS UVB-caused HLE-B3 cells death, lens opacity and lipid peroxidation could be mitigated by ferroptosis inhibitors. Grx2 KO mice accelerate the appearance of lens opacity induced by UVB. Meanwhile, Grx2 silencing enhanced HLECs lipid peroxidation susceptibility, downregulated the GSH level, shrunk mitochondria, and reduced the number of cristae. Grx2 overexpression had opposite effects. CONCLUSIONS Ferroptosis appears involved in UVB-induced HLECs damage. Inhibiting ferroptosis prevented UVB-induced cataracts. Grx2 strengthens resistance to ferroptosis induced by UVB irradiation through maintaining HLEC cellular GSH/GSSG homeostasis.
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Affiliation(s)
- Chenjun Guo
- Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, Shaanxi, 710004, China; Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Yong Guo
- Xi'an Purui Eye Hospital, Xi'an, Shaanxi, 710068, China
| | - Jie Zhang
- Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Jue Wang
- Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Liping Su
- Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, Shaanxi, 710004, China
| | - Xiaona Ning
- Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Xi Chen
- Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, Shaanxi, 710004, China
| | - Hong Yan
- Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, Shaanxi, 710004, China; Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, China.
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Yu H, Zhou C, Yang S, Yu J, Zhang X, Liang Z, Tan S, Song Y, Wang W, Sun Y, Zan R, Qiu H, Shen L, Zhang X. Mitigation of arteriosclerosis through transcriptional regulation of ferroptosis and lipid metabolism by magnesium. Biomaterials 2025; 319:123135. [PMID: 39985976 DOI: 10.1016/j.biomaterials.2025.123135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 02/24/2025]
Abstract
Metallic cardiovascular stents are crucial for preventing atherosclerosis-induced infarction by offering mechanical support. However, the effects of metal ions released from these stents on atherosclerosis remain ambiguous. This study evaluates the potential impact posed by the degradation products of magnesium-based stents, with a focus on ferroptosis, a key mechanism driving atherosclerosis. Remarkably, our results demonstrate that Mg effectively inhibits ferroptosis in human umbilical vein endothelial cells and in murine, rat and rabbit models. Our studies reveal that magnesium ions impede the dephosphorylation of ERK proteins, thereby enhancing the expression of SLC7A11 and GCL proteins via activation of the MAPK pathway mechanistically. Additionally, magnesium ions downregulate ACSL4 protein expression, leading to decreased levels of acyl-CoA and ether-phospholipids. Eventually, multiple animal experiments indicate that biodegradable Mg stents can inhibit ferroptosis and decelerate the progression of arteriosclerosis, highlighting the therapeutic potential of Mg stents in treating arteriosclerosis.
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Affiliation(s)
- Han Yu
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Changyi Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, 200030, China
| | - Shi Yang
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jinlong Yu
- Orthopaedic Department, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Xiyue Zhang
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhaojia Liang
- Stomatologic Hospital and College, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, Anhui, 230032, China
| | - Shuang Tan
- Stomatologic Hospital and College, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, Anhui, 230032, China
| | - Yang Song
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Wenhui Wang
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China
| | - Yu Sun
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Rui Zan
- Yiwu Research Institute of Fudan University, Fudan University, Yiwu, Zhejiang, 322000, China.
| | - Hua Qiu
- Stomatologic Hospital and College, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, Anhui, 230032, China.
| | - Li Shen
- Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, 200030, China.
| | - Xiaonong Zhang
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
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Wang H, Zhang W, Sun Y, Xu X, Chen X, Zhao K, Yang Z, Liu H. Nanotherapeutic strategies exploiting biological traits of cancer stem cells. Bioact Mater 2025; 50:61-94. [PMID: 40242505 PMCID: PMC12002948 DOI: 10.1016/j.bioactmat.2025.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 03/08/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.
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Affiliation(s)
- Hongyu Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Wenjing Zhang
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Yun Sun
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Xican Xu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Xiaoyang Chen
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Kexu Zhao
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Zhao Yang
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Huiyu Liu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
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Xu H, Wu Z, Tang J, Gan Y, Li J, Yu Y, Chen Y, Sui R, Liu J, Zhang Y, Piao H. Ginsenoside F2-modified liposomes delivering FTY720 enhance glioblastoma targeting and antitumor activity via ferroptosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 144:156917. [PMID: 40480023 DOI: 10.1016/j.phymed.2025.156917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 05/19/2025] [Accepted: 05/26/2025] [Indexed: 06/22/2025]
Abstract
BACKGROUND Glioblastoma (GBM) is the most malignant primary intracranial tumor. Owing to its unfavorable prognosis and frequent recurrence, patient outcomes are poor even with standard treatment. Recent studies have reported that FTY720, a structurally modified sphingosine extracted from Cordyceps sinensis, has preclinical antitumor efficacy and can regulate the microenvironment of GBM. However, the mechanism and effective utilization of FTY720, i.e., avoiding adverse reactions during systemic application in GBM remain unclear. PURPOSE This study aimed to investigate the mechanisms by which FTY720 suppresses GBM growth and to explore the ability of a novel liposomal nanoparticle carrying FTY720 to directly target GBM. METHODS Molecular, cytological, and histological techniques were employed to assess the effects of FTY720 on GBM cells, both in vitro and in vivo. Ferroptosis induction and its regulatory mechanisms were explored using a combination of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) assays; transmission electron microscopy (TEM); and orthotopic GBM mouse model experiments. A nanoparticle drug delivery system based on liposomes (GF2-FTY720-LPs) was synthesized by thin film dispersion. RESULTS Our study revealed that FTY720 induces ferroptosis in GBM cells through the AMPK-mTOR-GPX4 pathway, and that ginsenoside F2 (GF2) plays a synergistic role by reducing GSH levels. GF2-FTY720-LPs show superior targeting ability and potent inhibition of GBM in vivo, penetrating the blood-brain barrier and overcoming the shortcomings of systemic FTY720 application. CONCLUSION Our findings revealed the inhibitory effect of FTY720 on GBM, and the great ability of GF2-FTY720-LPs to target GBM. GF2-FTY720-LPs penetrate the blood-brain barrier without relying on specific conditions such as a magnetic field, light, or heat. GF2-FTY720-LPs achieved precise localization by targeting the highly expressed GLUT1 in GBM cells, and efficiently released drugs in the acidic tumor microenvironment, which significantly reduced the off-target toxicity and enhanced the antitumor efficacy compared with traditional chemotherapy drugs. In summary, our study provides new insights and a theoretical basis for selecting and researching GBM treatment.
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Affiliation(s)
- Huizhe Xu
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China; Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Ganjingzi District, Dalian 116024, Liaoning Province, P R PR China.
| | - Zhisheng Wu
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China; Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Jiamei Tang
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China; Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Yu Gan
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China; Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Jicheng Li
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China; Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Yingying Yu
- Central Laboratory, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China; Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Yi Chen
- Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Rui Sui
- Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Jia Liu
- Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Ye Zhang
- Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
| | - Haozhe Piao
- Institute of Cancer Medicine, Dalian University of Technology, No.2 Linggong Road, Ganjingzi District, Dalian 116024, Liaoning Province, P R PR China; Department of Neurosurgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning Province, P R PR China.
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Zhang Q, Xu Z, Liu W, Cheng Z, Ding Y, Xie Y, Yan S. Gastrodin promotes ferroptosis in CRC cells by inhibiting SKP2 to reduce NCOA4 ubiquitination. Tissue Cell 2025; 95:102793. [PMID: 40048831 DOI: 10.1016/j.tice.2025.102793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/28/2025] [Accepted: 02/10/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Gastrodin, an important component of traditional Chinese medicine, is gaining interest because of its anti-tumor effects. Ferroptosis is a new mode of cell death, which has emerged as a promising target for colorectal cancer (CRC) treatment. This research investigates the action mechanism of gastrodin on the process of CRC by inducing ferroptosis. METHODS The mRNA and protein levels were measured via qRT-PCR and western blot. Cell viability was assessed by CCK-8 assay. The cell proliferation was examined using colony formation assay. Live-Dead cell staining was evaluated by Calcein-AM/PI staining. The effect of ferroptosis was evaluated by detecting the levels of reactive oxygen species (ROS), intracellular total iron, ferrous iron (Fe2 +), malondialdehyde (MDA), glutathione (GSH) by kits, as well as the expressions of subunit solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferritin light chain (FTL) and acyl-CoA synthetase long chain family member 4 (ACSL4) by western blot. Co-immunoprecipitation (Co-IP) assay was applied to analyze the binding relationship between S-phase kinase-associated protein 2 (SKP2) and nuclear receptor coactivator 4 (NCOA4). RESULTS Gastrodin could induce ferroptosis in CRC cells. SKP2 ameliorated gastrodin induced ferroptosis in CRC cells. Besides, SKP2 mediated NCOA4 degradation by ubiquitination. SKP2 was involved in ferroptosis of CRC cells by regulating NCOA4. Gastrodin induced ferroptosis in CRC cells via SKP2/NCOA4 axis. CONCLUSION Gastrodin repressed SKP2 expression, deactivated NCOA4 ubiquitination thus elevated NCOA4 expression, and promoted ferroptosis in CRC cells.
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Affiliation(s)
- Qiao Zhang
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Zhijie Xu
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Wanying Liu
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Zhidong Cheng
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Yating Ding
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Yafeng Xie
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Shengyu Yan
- Department of Proctology, the Second Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China; Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Mavaddatiyan L, Naeini S, Khodabandeh S, Hosseini F, Skelton RP, Azizi V, Talkhabi M. Exploring the association between aging, ferroptosis, and common age-related diseases. Arch Gerontol Geriatr 2025; 135:105877. [PMID: 40339241 DOI: 10.1016/j.archger.2025.105877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 04/14/2025] [Accepted: 04/26/2025] [Indexed: 05/10/2025]
Abstract
Aging is a natural biological process that is characterized by the progressive decline in physiological functions and an increased vulnerability to age-related diseases. The aging process is driven by different cell and molecular mechanisms. It has recently been shown that aging is associated with heightened vulnerability to ferroptosis (an intracellular iron-dependent form of programmed cell death). This susceptibility arises from various factors including oxidative stress, impaired antioxidant defences, and dysregulated iron homeostasis. The progressive decline in cellular antioxidant capacity and the accumulation of damaged components contribute to the increased susceptibility of aging cells to ferroptosis. Dysregulation of key regulators involved in ferroptosis, such as glutathione peroxidase 4 (GPX4), iron regulatory proteins, and lipid metabolism enzymes, further exacerbates this vulnerability. The decline in cellular defence mechanisms against ferroptosis during aging contributes to the accumulation of damaged cells and tissues, ultimately resulting in the manifestation of age-related diseases. Understanding the intricate relevance between aging and ferroptosis holds significant potential for developing strategies to counteract the detrimental effects of aging and age-related diseases. This will subsequently act to mitigate the negative consequences of aging and improving overall health in the elderly population. This review aims to clarify the relationship between aging and ferroptosis, and explores the underlying mechanisms and implications for age-related disorders, including neurodegenerative, cardiovascular, and neoplastic diseases. We also discuss the accumulating evidence suggesting that the imbalance of redox homeostasis and perturbations in iron metabolism contribute to the age-associated vulnerability to ferroptosis.
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Affiliation(s)
- Laleh Mavaddatiyan
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - SaghiHakimi Naeini
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Sara Khodabandeh
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Fatemeh Hosseini
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - RhysJ P Skelton
- Flinders Medical Centre, Department of Ophthalmology, Bedford Park, Australia
| | - Vahid Azizi
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mahmood Talkhabi
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
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Zhang Z, Tang J, Liu Y, Wang Y, Li J, Gao Y, Cheng C, Su S, Chen S, Ai S, Zhang P, Lu R. The role of lactate metabolism in retinoblastoma tumorigenesis and ferroptosis resistance. Tissue Cell 2025; 95:102893. [PMID: 40188688 DOI: 10.1016/j.tice.2025.102893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 05/15/2025]
Abstract
The Warburg effect, a hallmark of cancer, describes the preference of cancer cells for glucose metabolism via aerobic glycolysis, leading to substantial lactate accumulation. However, the role of lactate metabolism in retinoblastoma, the primary intraocular malignancy in children, remains unclear. This study aimed to elucidate the gene expression profiles associated with lactate metabolism in retinoblastoma and their impact on tumorigenesis and ferroptosis resistance. The involvement of metabolic characteristics in retinoblastoma was analyzed by comparing single-cell RNA sequencing transcriptome profiles from normal retina tissues and retinoblastoma tissues from patient samples. The effects of lactate on retinoblastoma cell line viability and its mechanisms were examined both in vitro and in vivo. Single-cell RNA sequencing analysis revealed enhanced glycolysis in retinoblastoma cells and significant differences in lactate metabolism-related gene expression among various retinoblastoma cell types. Retinoblastoma cell lines with moderate lactate levels exhibited increased viability and resistance to ferroptosis induced by ferroptosis inducers. Additionally, lactate promoted the upregulation of monocarboxylate transporter 1 (MCT1), which facilitated lactate transport, in a dose-dependent manner in retinoblastoma cell lines. Knocking down MCT1 reduced both viability and ferroptosis resistance of retinoblastoma cell lines in a lactate-rich environment. In vivo, disrupting lactate transport through MCT1 inhibition suppressed retinoblastoma tumorigenesis and invasion in a mouse xenograft model, and this effect was reversed by the ferroptosis inhibitor liproxstatin-1. These findings highlighted the crucial role of lactate metabolism in retinoblastoma tumorigenesis and resistance to ferroptosis.
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Affiliation(s)
- Zhihui Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Junjie Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Yaoming Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Yinghao Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Jinmiao Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Yang Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Chao Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Shicai Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Shuxia Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Siming Ai
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Ping Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China
| | - Rong Lu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China.
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Shan GY, Shi YP, Zhang YX, Wan H, Gao ZC, Li HJ. Ginsenoside Rg5 ameliorates lipopolysaccharide (LPS)-induced acute liver injury via interfering Autophagy/Nrf2/Ferroptosis signal axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 144:156941. [PMID: 40516288 DOI: 10.1016/j.phymed.2025.156941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 04/24/2025] [Accepted: 06/01/2025] [Indexed: 06/16/2025]
Abstract
BACKGROUND Ginseng is a widely known Chinese herb, exerts its pharmacological effects primarily through ginsenosides. Ginsenoside-Rg5 is isolated from ginseng, has been shown to protect the liver and activate Nrf2 expression. PURPOSE The protective effect of Rg5 on acute liver injury (ALI) and the related mechanisms will be discussed. METHODS In vitro experiments, an ALI model was established using HepG2 cells. The DCFH-DA, the JC-1 and the ferrous ion fluorescent probe detected the ROS level, the mitochondrial membrane potential change, and the iron ions level. The oxidative stress indexes were detected by biochemical analysis. Western Blot was used to detected the autophagy, Nrf2, and ferroptosis signaling pathways. In vivo experiments, C57BL/6 J mice were injected with LPS to create ALI model. RESULTS In vitro, Rg5 significantly inhibited the production of ROS, while restoring mitochondrial membrane potential. Biochemical analysis showed that Rg5 increased the SOD and GSH levels while decreased the MDA and ferric ion significantly. In vivo, Rg5 reduced the liver/body ratio, serum ALT and AST levels. Rg5 suppressed autophagy-related protein expression, promote Nrf2 and the ferroptosis negative regulatory proteins. This study first confirms that Rg5 exerts a protective effect on the liver by inhibiting ferroptosis, enriching the pharmacological properties of Rg5. CONCLUSION The protective role of Rg5 against LPS-triggered ALI was mediated via autophagy/Nrf2-dependent suppression of ferroptosis.
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Affiliation(s)
- Guan-Yue Shan
- Laboratory for Tumor Immunology, The First Hospital of Jilin University, Changchun 130061, PR China; Department of Bioengineering, Jilin University School of Pharmaceutical Sciences, Changchun 130021, PR China
| | - Yun-Peng Shi
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China
| | - Yu-Xin Zhang
- Laboratory for Tumor Immunology, The First Hospital of Jilin University, Changchun 130061, PR China; Institute of Ginseng Research, Jilin University, Changchun 130021, PR China; China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Hui Wan
- Laboratory for Tumor Immunology, The First Hospital of Jilin University, Changchun 130061, PR China; Institute of Ginseng Research, Jilin University, Changchun 130021, PR China; China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Zhi-Cheng Gao
- Laboratory for Tumor Immunology, The First Hospital of Jilin University, Changchun 130061, PR China; Institute of Ginseng Research, Jilin University, Changchun 130021, PR China; China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Changchun 130021, PR China
| | - Hai-Jun Li
- Laboratory for Tumor Immunology, The First Hospital of Jilin University, Changchun 130061, PR China; Institute of Ginseng Research, Jilin University, Changchun 130021, PR China; China-Singapore Belt and Road Joint Laboratory on Liver Disease Research, The First Hospital of Jilin University, Changchun 130021, PR China.
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Liu W, Zhang J, Wu M, Ren D, Chen C, Du Z, Li Q, Chang J, Pu Q, Liu Z. Ponicidin triggered ferroptosis in esophageal squamous cell carcinoma by suppressing the SLC7A11/Glutathione/GPX4 signalling axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156925. [PMID: 40456202 DOI: 10.1016/j.phymed.2025.156925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 05/17/2025] [Accepted: 05/27/2025] [Indexed: 06/16/2025]
Abstract
BACKGROUND Ponicidin, a diterpenoid derived from Rabdosia rubescens, exhibits potent antitumor activity. However, its mechanisms against esophageal squamous cell carcinoma (ESCC) remain obscure. This study aims to explore the effects of ponicidin against ESCC and reveal its molecular mechanisms. METHODS The anti-ESCC effects of ponicidin were evaluated using CCK-8 assay, colony formation and transwell invasion assays. Cell cycle progression and mitochondrial membrane potential were analyzed using flow cytometry. Proteomics was applied to explore ponicidin's mechanisms. Ferroptosis induction was evaluated by quantifying reactive oxygen species, Fe2+, malondialdehyde, glutathione, and lipid peroxidation levels. Docking and molecular dynamics simulations were conducted to identify the targets. siRNA was employed to validate target. The efficacy of ponicidin on tumorigenicity was explored in tumor xenograft mouse models, and its biosafety was evaluated via hemolysis assays, plasma ALT, AST, BUN, and CRE levels, as well as histopathological examinations. Western blot was used to analyze protein expression levels. RESULTS Ponicidin inhibited ESCC cell proliferation, arrested cells in the G2/M phase, reduced mitochondrial membrane potential, and suppressed tumor growth without evident toxicity. Proteomics identified that ponicidin-induced ferroptosis is the predominant mechanism against ESCC. Ponicidin increased reactive oxygen species, malondialdehyde, Fe2+, lipid peroxidation and glutathione depletion. Ferrostatin-1 pretreatment reduced lipid peroxidation, rescued PON induced inhibition of cell viability, and reversed the decreased expression of SLC7A11, GPX4 and GSR. Molecular docking revealed strong binding affinity of PON to GPX4 (-7.31±0.55 kcal/mol) and SLC7A11 (-8.19±0.37 kcal/mol). Molecular dynamics simulations confirmed stabilized complexes with total interaction energies of -23.43 ± 2.13 kcal/mol (GPX4-PON) and -31.42 ± 0.84 kcal/mol (SLC7A11-PON). siRNA-mediated knockdown of GPX4 and SLC7A11 reduced ESCC sensitivity to ponicidin-induced ferroptosis. CONCLUSION This study provides the first evidence that ponicidin triggers ferroptosis in ESCC cells via suppression of the SLC7A11/glutathione/GPX4 signalling axis, offering actionable targets for ferroptosis-enhancing combination therapies.
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Affiliation(s)
- Wenhu Liu
- School of Pharmacy, North Sichuan Medical College, Nanchong, 637100, China.
| | - Jinhua Zhang
- School of Pharmacy, North Sichuan Medical College, Nanchong, 637100, China; Innovation Center for Science and Technology, North Sichuan Medical College, Nanchong, 637100, China
| | - Min Wu
- School of Pharmacy, North Sichuan Medical College, Nanchong, 637100, China; Innovation Center for Science and Technology, North Sichuan Medical College, Nanchong, 637100, China
| | - Dan Ren
- School of Pharmacy, North Sichuan Medical College, Nanchong, 637100, China; Innovation Center for Science and Technology, North Sichuan Medical College, Nanchong, 637100, China
| | - Chuan Chen
- School of Pharmacy, North Sichuan Medical College, Nanchong, 637100, China
| | - Zuo Du
- School of Public Health, North Sichuan Medical College, Nanchong, 637100, China
| | - Qianhui Li
- School of Pharmacy, North Sichuan Medical College, Nanchong, 637100, China
| | - Jinxia Chang
- School of Basic Medical Sciences & Forensic Medical, North Sichuan Medical College, Nanchong, 637100, China
| | - Qi Pu
- Technology Innovation Center, Chong Qing Medical University, Chongqing, 400016, China
| | - Zhenzhong Liu
- School of Public Health, North Sichuan Medical College, Nanchong, 637100, China.
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Ge X, Fan YZ, Deng Y, Chen Y, Gao J, Zhu G, Liu Y, Li Y, Ge G, Liu HX. Pectolinarigenin mitigates 5-FU-induced intestinal mucositis via suppressing ferroptosis through activating PPARγ/GPX4 signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156843. [PMID: 40414047 DOI: 10.1016/j.phymed.2025.156843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 04/10/2025] [Accepted: 05/11/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND 5-Fluorouracil (5-FU), one of the mostly commonly used chemotherapeutic agents, frequently induces intestinal mucositis, severely impacting patient quality of life and limiting treatment efficacy. Pectolinarigenin (PEC), a bioactive compound isolated from Chinese medicinal herb Dajitan, exhibits anti-inflammatory, antioxidative, and anticancer properties. However, its protective effect on 5-FU-induced mucositis and the underlying molecular mechanisms remains unclear. PURPOSES To investigate the therapeutic effects and underlying mechanisms of PEC in 5-FU-induced intestinal mucositis. METHODS Mouse models of ileal and colonic injury were used to study 5-FU-induced mucositis. Histological and biochemical assays assessed mucositis severity. A panel of 71 antioxidants was screened for their ability to inhibit 5-FU-induced cells death. Transcriptome sequencing, molecular docking, molecular dynamics simulations, and Western blotting explored PEC's mechanism of action, with a focus on its role in activating the PPARγ signaling pathway. Meanwhile, 5-aminosalicylic acid (5-ASA, the first-line therapeutic agent for treating ulcerative colitis) and pioglitazone (a known PPARγ agonist) were used as positive controls. RESULTS 5-FU induced ferroptosis and intestinal inflammation both in vivo and in vitro, characterized by increased iron and ROS accumulation, reduced GSH levels, and elevated lipid peroxidation biomarkers. Histological analysis showed severe intestinal mucosal damage. Among all tested phytochemicals, PEC demonstrated the best ameliorative effects on 5-FU-induced mucositis, showing impressive therapeutic efficacy in both cellular and animal models. PEC significantly mitigated 5-FU induced mucositis via reducing iron accumulation, lowering ROS and MDA levels, restoring GSH, and normalizing ferroptosis-related markers. Transcriptomic analysis combined cellular assays revealed that the PPARγ signaling plays a critical role in the protective effects of PEC against 5-FU-induced intestinal cellular injury. Further investigations showed that PEC could activate the PPARγ/GPX4 signaling pathway both in vitro and in vivo, which in turn, restored tight junction integrity and suppressed intestinal ferroptosis, ultimately providing protective effects against 5-FU-induced intestinal injury. CONCLUSIONS This study uncovers a previously unrecognized ferroptosis-related mechanism underlying 5-FU-induced intestinal mucositis, while PEC significantly mitigates 5-FU-induced intestinal mucositis by activating the PPARγ/GPX4 axis. Our findings suggest that activating the PPARγ/GPX4 signaling pathway using phytochemicals represents a promising therapeutic strategy for mitigating chemotherapy-induced intestinal mucositis.
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Affiliation(s)
- Xin Ge
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning, China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning, China
| | - Yi-Zhe Fan
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning, China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning, China; Institute of Life Sciences, China Medical University, Shenyang 110122, Liaoning, China
| | - Yanyan Deng
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yutao Chen
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning, China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning, China; Institute of Life Sciences, China Medical University, Shenyang 110122, Liaoning, China
| | - Jian Gao
- Science Experiment Center, China Medical University, Shenyang 110122, Liaoning Province, China
| | - Guanghao Zhu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yili Liu
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of Bladder Disease Gene Research, Institute of Health Science, China Medical University, Shenyang, China
| | - Yongzhi Li
- Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Liaoning Key Laboratory of Bladder Disease Gene Research, Institute of Health Science, China Medical University, Shenyang, China.
| | - Guangbo Ge
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Hui-Xin Liu
- Health Sciences Institute, China Medical University, Shenyang 110122, Liaoning, China; Liaoning Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang 110122, Liaoning, China; Institute of Life Sciences, China Medical University, Shenyang 110122, Liaoning, China; Liaoning Key Laboratory of Bladder Disease Gene Research, Institute of Health Science, China Medical University, Shenyang, China.
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Yang B, Qu W, Lu J, Wu Z, Li Y, Yao R, Wang J, Li Y, Lu Z, Geng Z, Wang Z. Red-emitting aggregation-induced emission fluorescent probe for monitoring fluctuation of HClO in mitochondria during ferroptosis. Anal Chim Acta 2025; 1360:344140. [PMID: 40409902 DOI: 10.1016/j.aca.2025.344140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/25/2025]
Abstract
BACKGROUND Ferroptosis is an iron-dependent programmed cell death pathway driven by lipid peroxidation that involves various inflammation-related diseases and even cancer, which is often accompanied by the accumulation of mitochondrial ROS. HClO, as one of the vital ROS in organisms, is mainly derived from the mitochondria of cells. And abnormal levels of HClO can disrupt redox homeostasis in cells and lead to various diseases. Importantly, intracellular HClO levels are also associated with ferroptosis. Therefore, it is very important to study the fluctuation of intracellular HClO level during ferroptosis. RESULTS Herein, a HClO fluorescent probe TPA-ClO was synthesized using triphenylamine fluorophore and benzothiadiazole structure. Notably, TPA-ClO exhibited the advantages of NIR fluorescence emission, good AIE properties and large Stokes shift, and which could selectively detect HClO with a detection limit of 150.0 nM. TPA-ClO could be well targeted in mitochondria and had been successfully applied to monitor exogenous and endogenous HClO in MCF7 cells. Moreover, the imaging experiment of TPA-ClO indicated that erastin- and RSL3-induced ferroptosis in MCF7 cells led to increased levels of mitochondrial HClO and that MCF7 cells showed high ferroptosis sensitivity to RSL3. SIGNIFICANCE TPA-ClO exhibited high selectivity to HClO over other potential interfering substances, and could be employed to monitor HClO level fluctuations in MCF7 cells. More importantly, TPA-ClO could be an effective tool to monitor the fluctuations of HClO level in mitochondria during ferroptosis as well as for investigating various diseases associated with ferroptosis for future research.
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Affiliation(s)
- Bin Yang
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Wangbo Qu
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Jiao Lu
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Zhou Wu
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Yong Li
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Ruihong Yao
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Jun Wang
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Yanli Li
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Zhihao Lu
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China
| | - Zhirong Geng
- College of Pharmacy, Jiangsu Joint International Laboratory of Animal-Derived Chinese Medicine and Functional Peptides, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
| | - Zhilin Wang
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210023, PR China.
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Bi T, Koch H, Kremer B, Höllig A. Iron Hemostasis in Patients With Subarachnoid Hemorrhage and the Role of Early CSF Drainage. Neurology 2025; 105:e213767. [PMID: 40489716 DOI: 10.1212/wnl.0000000000213767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 04/03/2025] [Indexed: 06/11/2025] Open
Abstract
Early brain injury and delayed cerebral ischemia are combined intricate processes, and they represent the principal cause of subarachnoid hemorrhage (SAH)-related morbidity and mortality worldwide. Recent studies have shown that early lumbar CSF drainage can be used to decrease the incidence of delayed cerebral ischemia and improve long-term outcome. This approach has provided novel insights into post-SAH management that lessened the burden of secondary infarction and decreased the rate of unfavorable outcome. Given that the evaluation of this approach is contingent on prospective trial and early-stage randomized clinical trial, we review insights from studies that have elucidated the mechanisms underlying deterioration in SAH. We explore the role of iron homeostasis in the restoration of normal CSF circulation and the stabilization of optimal cerebral physiology to alleviate early brain injury and delayed neurologic impairment after SAH to advance the current understanding of SAH management.
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Affiliation(s)
- Tianshu Bi
- Department of Neurosurgery, Medical Faculty, RWTH Aachen University, Germany; and
| | - Henner Koch
- Department of Epileptology, Neurology, Medical Faculty, RWTH Aachen University, Germany
| | - Benedikt Kremer
- Department of Neurosurgery, Medical Faculty, RWTH Aachen University, Germany; and
| | - Anke Höllig
- Department of Neurosurgery, Medical Faculty, RWTH Aachen University, Germany; and
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Luo Y, Yao M, Wang R, Liao S, Yu J. Netrin-1 binding to UNC5b improves post-stroke neuronal ferroptosis via AMPK-BACH1 pathway. Eur J Pharmacol 2025; 998:177507. [PMID: 40086580 DOI: 10.1016/j.ejphar.2025.177507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
Ferroptosis contributes to neuronal destruction after ischemic stroke which may be improved by inhibiting BTB domain and CNC homolog 1 (BACH1), a recently recognized ferroptosis facilitator. Axon guidance molecule netrin-1 (Ntn1) functions in neuroprotection against ischemic insult by engaging into its receptor of uncoordinated-5 homolog B (UNC5b) via adenosine 5'-monophosphate-activated protein kinase (AMPK), which potentially binds to BACH1. Whether Ntn1/UNC5b regulates post-stroke ferroptosis through AMPK-BACH1 pathway remains unclear. Ntn1 supplementation and UNC5b knockdown by siRNA were performed in photo-thrombosis stroke mice and oxygen-glucose deprivation-treated HT22 neurons. AMPK inhibitor BAY3827 and BACH1 activator Leptomycin B (LMB) were administrated. Ferroptosis was determined by ferroptosis-associated proteins (FSP1, GPX4 and ACSL4), Fe2+, malondialdehyde and mitochondrial morphology. BACH1 and p-AMPK/AMPK as well as the interaction between them were examined by Western blot and co-immunoprecipitation. Neuronal ferroptosis and the protein levels of BACH1 and p-AMPK were increased after photo-thrombosis and oxygen-glucose deprivation. Ntn1 supplementation or UNC5b knockdown relieved neuronal ferroptosis and neurological impairment with downregulated BACH1 and upregulated p-AMPK, nonetheless, UNC5b knockdown prevented the beneficial role of Ntn1. Both BAY3827 and LMB could reverse the change of ferroptosis caused by Ntn1 where BAY3827 inhibited the effects of Ntn1 to p-AMPK and BACH1 while LMB only inhibited the effect of Ntn1 to BACH1 without p-AMPK, suggesting BACH1 was regulated by AMPK. Co-immunoprecipitation verified that AMPK could physically bind to BACH1. Our results demonstrate UNC5b-evoked neuronal ferroptosis post stroke, and favor that Ntn1 improves post-stroke ferroptosis by its interaction with UNC5b via the AMPK-BACH1 pathway.
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Affiliation(s)
- Ying Luo
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China; Department of Neurology, The Affiliated Hospital of Southwest Medical University, Laboratory of Neurological Diseases and Brain Function, Luzhou, 646000, China
| | - Meiling Yao
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China
| | - Rui Wang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China
| | - Songjie Liao
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China.
| | - Jian Yu
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases; National Key Clinical Department and Key Discipline of Neurology, No.58 Zhongshan Road 2, Guangzhou, 510080, China.
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Zhong M, Zhong S, Qiu K, Peng X, Liu X, Sui S, Dai Z, Wang X, Nie D, Yu Z, Yu Q, Chen C, Li Y, Zeng C. Synergistic effects of BET inhibitors and ferroptosis inducers via targeted inhibition of the BRD4/c-Myc/NRF2 pathway in AML. Eur J Pharmacol 2025; 998:177652. [PMID: 40252902 DOI: 10.1016/j.ejphar.2025.177652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/13/2025] [Accepted: 04/17/2025] [Indexed: 04/21/2025]
Abstract
In acute myeloid leukemia (AML), high expression of BRD4 is associated with poor prognosis. BET inhibitors that mainly inhibit BRD4 can induce AML cell death, but some AML cells are insensitive to BET inhibitors. We found that BET inhibitors could promote the up-regulation of the ferroptosis signaling pathway in AML. In this study, we intend to investigate the synergistic effects of BET inhibitors with ferroptosis inducers in AML cells. The combination of BET inhibitors with ferroptosis inducers (RSL3, FIN56, and Erastin) markedly reduced AML cell viability and increased cell death, as demonstrated by CCK-8 assays and flow cytometry analysis across multiple AML cell lines and primary AML patient samples. Moreover, BET inhibitors combined with ferroptosis inducers elevated the lipid reactive oxygen species (ROS) levels, indicating heightened lipid peroxidation, a hallmark of ferroptosis. Mechanistically, BET inhibitor and ferroptosis inducer co-targeted the BRD4/c-Myc/NRF2 axis, leading to downregulation of NRF2, key regulators of AML cell survival and oxidative stress resistance. NRF2 knockdown amplified the anti-AML effect of this combined treatment, whereas NRF2 overexpression negated this synergy, highlighting its critical role in mediating ferroptosis resistance. Finally, survival analyses of AML patients from the TCGA and GSE71014 datasets revealed that elevated expression of BRD4, NRF2, and its downstream target GPX4, an essential ferroptosis regulator, correlated with poor overall survival, highlighting the clinical relevance of our findings. In all, combining BET inhibition with ferroptosis induction could enhance anti-leukemia effect and represent a novel therapeutic strategy for targeting AML cells.
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Affiliation(s)
- Mengjun Zhong
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China; Department of Hematology, Guangzhou First People's Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical University, Guangzhou, 510180, PR China
| | - Shuxin Zhong
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Kangjie Qiu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Xueting Peng
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Xin Liu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Songnan Sui
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China; Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, PR China
| | - Zhangshuai Dai
- Department of Hematology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, PR China
| | - Xianfeng Wang
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Dingrui Nie
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China
| | - Zhi Yu
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, PR China
| | - Quan Yu
- Experimental Research Center, School of Medicine, Jinan University, Guangzhou, 510632, PR China.
| | - Cunte Chen
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China; Department of Hematology, Guangzhou First People's Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical University, Guangzhou, 510180, PR China.
| | - Yangqiu Li
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China.
| | - Chengwu Zeng
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, PR China; Department of Hematology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, PR China.
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Xu H, Mao X, Mo D, Lv M. 6PPD impairs growth performance by inducing intestinal oxidative stress and ferroptosis in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 2025; 293:110161. [PMID: 39988222 DOI: 10.1016/j.cbpc.2025.110161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), a tire-derived pollutant, has gained increasing attention due to its potential toxicity to aquatic organisms. Although previous studies have revealed that 6PPD impacts early developmental stages of larval fish, its effects on adult fish, particularly on key organs, remain unclear. In this study, we observed that adult zebrafish exposed to 6PPD exhibited reduced growth performance and increased fecal output. Histological examination with hematoxylin and eosin (H&E) staining revealed damage to the intestinal villi and a reduction in goblet cell numbers, indicating that 6PPD impairs growth performance by disrupting the digestive system. Comparative transcriptomic analysis revealed that 6PPD caused significant changes in the expression of 727 genes in the intestine, of which 280 genes were up-regulated and 447 genes were down-regulated. These genes were primarily associated with nutrient digestion and absorption, energy metabolism, immune response, and redox regulation. Mechanistically, 6PPD induced oxidative stress and triggered ferroptosis in the intestine, leading to structural damage of the intestinal villi. Treatment with the antioxidant N-acetylcysteine (NAC) alleviated 6PPD-induced oxidative stress and ferroptosis, thereby improving intestinal villi structure and promoting fish growth. This study provides insights into the mechanisms by which 6PPD impairs growth in adult zebrafish and highlights NAC as a potential therapeutic strategy to mitigate its toxicity.
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Affiliation(s)
- Hao Xu
- Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City & Aquaculture Engineering Technology Research Center, College of Fisheries, Southwest University, Chongqing 400715, China.
| | - Xiaoyu Mao
- College of Language Intelligence, Sichuan International Studies University, Chongqing 400031, China
| | - Dashuang Mo
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550025, China.
| | - Mengzhu Lv
- Department of Immunology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou 550025, China.
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Wang T, Liu Q, Wu L, Wang L, Jiang Z, Yue Y, Jiang P, Ji Z, Yin M, Zhang N, Han H. Endoplasmic reticulum stress-autophagy axis is involved in copper-induced ovarian ferroptosis. Free Radic Biol Med 2025; 234:1-18. [PMID: 40194638 DOI: 10.1016/j.freeradbiomed.2025.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/02/2025] [Accepted: 04/04/2025] [Indexed: 04/09/2025]
Abstract
Copper (Cu) contamination has emerged a global public health problem due to the extensive use of Cu in industrial production and daily life. Reproductive damage resulting from Cu exposure has been particularly evident. Wilson's disease (WD) is a recessive genetic disease characterized by impaired Cu metabolism. Female WD patients have often been associated with reproductive impairment. Ferroptosis, a form of iron-dependent regulated cell death, has been identified as being caused by massive lipid peroxide-mediated membrane damage. However, it remains unclear whether ferroptosis is associated with Cu-induced ovarian damage. In this study, the role of ferroptosis in ovarian damage induced by Cu accumulation and its underlying mechanisms were examined through both in vivo and in vitro experiments. The findings indicated that excessive Cu deposition in the ovaries could lead to follicular atresia and ovulation dysfunction, and trigger ferroptosis in ovarian and granulosa cells (GCs). The mechanism may be related to endoplasmic reticulum (ER) stress mediated by the protein kinase RNA-like ER kinase (PERK) pathway, and hyperactivation of autophagy. In addition, Cu-induced autophagy in GCs was found to increase intracellular iron levels via the ferritinophagy pathway, thereby inducing ferroptosis. We also found that mitochondrial reactive oxygen species (MitoROS) may be an onstream facilitator of Cu-induced ferroptosis via activation of the ER stress-autophagy pathway. Our findings suggested that ferroptosis is associated with Cu-induced ovarian damage and is regulated by the MitoROS-ER stress-autophagy axes. These results might provide insights for developing treatment for WD and other diseases related to Cu exposure.
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Affiliation(s)
- Tingting Wang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Qianzhuo Liu
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Limin Wu
- Center for Reproduction and Genetics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Luyao Wang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Zhenzhen Jiang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Yike Yue
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Pengyu Jiang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Zhihui Ji
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Miaozhu Yin
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Nian Zhang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China
| | - Hui Han
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, Anhui Province, China.
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Lin L, Huang D, Huang H, Xie L, Huang Y, Ye C, Chu L, Qiao Y, Meng X, Cai S, Dong H. Lung microbiota metabolite L-malic acid attenuates the airway inflammation in asthma by inhibiting ferroptosis. Toxicol Appl Pharmacol 2025; 500:117396. [PMID: 40381742 DOI: 10.1016/j.taap.2025.117396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 05/12/2025] [Accepted: 05/13/2025] [Indexed: 05/20/2025]
Abstract
Inhaled environmental allergens, such as house dust mites (HDM), have been shown to induce an inflammatory reaction, tissue injury, and increased airway sensitivity in the lungs, ultimately leading to the development of allergic asthma. The imbalance of respiratory microbiota and metabolites plays a crucial role in the progression of allergic asthma. However, there is limited knowledge available regarding the alterations in respiratory microbiota and metabolites and their impact on the host in the context of asthma. The aim of this study was to investigate the potential pathways involved in the development of asthma through the analysis of lung flora and metabolites. A mouse model of house dust mite (HDM)-induced asthma was established, and alveolar lavage samples were collected for microbiome 16S rRNA sequencing and untargeted metabolic analysis. Microbiological analyses indicated a significant alteration in the microbiota after 4 and 6 weeks of HDM nebulisation stimulation. This was characterized by a decrease in microbial diversity, as well as reductions in the relative proportion of Gallionella and Lactobacillus. Conversely, the abundance of Flavobacterium and Ralstonia increased in the HDM4W and HDM6W groups, respectively. Metabolomic analyses revealed seven distinct metabolites, among them L-malic acid, which were linked to signaling pathways in a mouse model of HDM-induced asthma. The correlation analysis demonstrated a positive association between L-malic acid and Rhodanobacter and Nocardioides. L-malic acid was discovered to be efficacious in reducing airway inflammation in mice with house dust mite-induced asthma. Further analysis revealed that this change was linked to lipid peroxidation and changes in ferroptosis markers, namely GPX4 and FTH. These findings suggest that L-malate inhibits ferroptosis. However, the introduction of ferroptosis inducers, such as Erastin, was observed to negate the beneficial effect of butyrate. In summary, this research implies that the respiratory microbiota metabolite L-malic acid lessens airway inflammation in asthma by inhibiting ferroptosis, offering a potential approach for managing asthma.
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Affiliation(s)
- Lishan Lin
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Respiratory and Critical Care Medicine of Puning People's Hospital, Puning, China
| | - Danhui Huang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haohua Huang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lingyan Xie
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Huang
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Cuiping Ye
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lanhe Chu
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yujie Qiao
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojing Meng
- School of Public Health, Southern Medical University, Guangzhou, China
| | - Shaoxi Cai
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Hangming Dong
- Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Yang Y, Li X, Xiao S, Wei Q, Ren L, Yao Y, Liu N. PARylation of POLG Mediated by PARP1 Accelerates Ferroptosis-Induced Vascular Calcification via Activating Adora2a/Rap1 Signaling. Arterioscler Thromb Vasc Biol 2025; 45:1175-1191. [PMID: 40401372 DOI: 10.1161/atvbaha.124.321682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 05/06/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Vascular calcification (VC) is associated with diabetes, chronic kidney disease, and aging. VC is found to be a powerful and independent risk factor for cardiovascular mortality. Vascular smooth muscle cell (VSMC) ferroptosis, a form of cell death, is known to be involved in VC. However, whether VSMC ferroptosis is regulated by posttranslational modifications remains undefined. METHODS We explored the potential role and mechanism of PARP1 (poly[ADP-ribose] polymerase 1)-mediated poly(ADP-ribosyl)ation (PARylation) in VSMC ferroptosis during VC. Mouse VSMCs were treated with β-glycerophosphate, and Parp1flox/flox Tagln Cre+ calcified mice were generated with AAV9-sh-POLG (DNA polymerase gamma) injected to establish in vitro and in vivo models, respectively. RNA-sequencing analysis was performed to determine the transcriptomic alterations in VSMCs overexpressing POLG and treated with β-glycerophosphate. RESULTS Both PARP1 expression and PARylation levels were increased in β-glycerophosphate-induced VC, with PARP1 knockdown mitigating VC by improving mitochondrial function and inhibiting the subsequent VSMC ferroptosis. Mechanistically, POLG PARylation levels were increased in calcified VSMCs from PARP1 activation, triggering PARylation-dependent ubiquitination of POLG that resulted in POLG downregulation. This led to mitochondrial dysfunction and Adora2a (adenosine receptor A2A)/Rap1 (Ras-associated protein 1) signaling pathway activation to induce VSMC ferroptosis, which ultimately aggravated VC. CONCLUSIONS Our study establishes the critical role of PARP1-mediated PARylation-dependent ubiquitination of POLG in VSMC ferroptosis-induced VC. These findings suggest that PARP1 inhibitors could potentially serve as novel therapeutic strategies for VC.
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Affiliation(s)
- Yiqing Yang
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Xiaoxue Li
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Shengjue Xiao
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Qin Wei
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Liqun Ren
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yuyu Yao
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
| | - Naifeng Liu
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
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Tianzhi L, Zhang Y, Liu X, Zuo Z. Fortunellin attenuates sepsis-induced acute kidney injury by inhibiting inflammation and ferroptosis via the TLR4/NF-κB pathway. Histol Histopathol 2025; 40:1083-1093. [PMID: 39544009 DOI: 10.14670/hh-18-841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
OBJECTIVE To investigate the potential protective effect of fortunellin in sepsis-induced acute kidney injury (AKI) and its underlying mechanisms. METHODS Lipopolysaccharide (LPS)-treated human kidney proximal tubular epithelial (HK-2) cells were used as a cell model and sepsis-induced AKI was induced by cecal ligation and puncture (CLP) surgery in mice. Cell Counting Kit-8 (CCK8) assays and flow cytometry analysis were performed to examine the viability of HK-2 cells. Enzyme-linked immunosorbent assay (ELISA) was performed to investigate the content of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in vivo and in vitro. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and free iron (Fe2+) were measured as indicators of ferroptosis. The phosphorylation levels of Interleukin-1 Receptor-Associated Kinase 4 (p-IRAK4), p65 (p-65), and inhibitor of kappa B alpha (p-IκBα) were detected by western blot as an indication of nuclear factor kappa-B (NF-κB) pathway activation. RESULTS Our cell and animal experiments revealed that fortunellin exhibits significant anti-inflammatory and cytoprotective properties. Fortunellin counteracted LPS-induced cellular damage in HK-2 cells, enhancing cell survival and suppressing the secretion of pro-inflammatory cytokines. Additionally, fortunellin demonstrated potent antioxidant effects, reducing MDA and Fe2+ levels while increasing SOD activity and GSH content. The protective effect of fortunellin was further corroborated in the mouse model of sepsis-induced AKI. Notably, fortunellin suppressed activation of the TLR4/NF-κB pathway in the AKI model, as evidenced by decreased levels of p-p65 and p-IκBα proteins. CONCLUSION Fortunellin ameliorates inflammation and oxidative stress in sepsis-induced AKI, possibly through the modulation of the TLR4/NF-κB pathway. These findings suggest fortunellin's potential as a therapeutic agent for sepsis-associated AKI.
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Affiliation(s)
- Liu Tianzhi
- Department of Critical Care Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, PR China
| | - Yanmin Zhang
- Department of Gastroenterology, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, PR China
| | - Xiujuan Liu
- Department of Critical Care Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, PR China
| | - Zhigang Zuo
- Department of Critical Care Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, PR China.
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50
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Liu Y, Feng LL, Han B, Cai LJ, Liu RY, Tang S, Yang Q. Exploring the molecular mechanisms through which overexpression of TET3 alleviates liver fibrosis in mice via ferroptosis in hepatic stellate cells. Cell Signal 2025; 131:111747. [PMID: 40096933 DOI: 10.1016/j.cellsig.2025.111747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/19/2025] [Accepted: 03/13/2025] [Indexed: 03/19/2025]
Abstract
Hepatic stellate cell (HSC) activation is crucial in the onset and progression of liver fibrosis, and inhibiting or eliminating activated HSCs is a key therapeutic strategy. Ferroptosis may help eliminate activated HSCs; however, its role and regulatory pathways in liver fibrosis remain unclear. As a DNA demethylase, TET3 regulates gene expression via DNA demethylation. We previously demonstrated that TET3 overexpression alleviates CCL4-induced liver fibrosis in mice; however, the specific mechanisms, including whether TET3 affects ferroptosis in HSCs, remain unexplored. Thus, we aimed to explore the molecular mechanisms wherein TET3 overexpression improves liver fibrosis in mice via ferroptosis in HSCs. Our in vivo observations showed that overexpression of TET3 ameliorate liver fibrosis in mice, and is associated with increased levels of malondialdehyde (MDA) and Fe2+ in liver tissue, as well as decreased protein expression of SLC7A11, GPX4, and FTH1. Further in vitro studies on HSCs showed that TET3 overexpression inhibits the expression of SLC7A11, GPX4, and FTH1, and reduces intracellular GSH levels, leading to accumulation of MDA and iron ions. This induces ferroptosis in HSC-LX2 cells, while simultaneously decreasing ECM accumulation in HSCs. Furthermore, hMeDIP-SEQ and ChIP-qPCR analyses revealed that TET3 directly interacts with the promoter regions of GPX4 and FTH1 to regulate their transcriptional expression. We propose that overexpression of TET3 modulates the gene methylation status of ferroptosis-related proteins, thereby regulating HSC ferroptosis, reducing activated HSCs, and decreasing ECM deposition in the liver. This may represent one of the molecular mechanisms wherein TET3 overexpression ameliorates liver fibrosis in mice.
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Affiliation(s)
- Yin Liu
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Lin-Lin Feng
- Center for Clinical Laboratories, Affiliated Hospital of Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Bing Han
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Li-Jun Cai
- Department of Rehabilitation Medicine, The Affiliated Hospital of Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Ran-Yang Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China
| | - Shuang Tang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China
| | - Qin Yang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, Guizhou, China.
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