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Wang L, He X, Shen Y, Chen J, Chen Y, Zhou Z, Xu X. A Novel Ferroptosis-Related Gene Prognosis Signature and Identifying Atorvastatin as a Potential Therapeutic Agent for Hepatocellular Carcinoma. Curr Issues Mol Biol 2025; 47:201. [PMID: 40136455 PMCID: PMC11940908 DOI: 10.3390/cimb47030201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/09/2025] [Accepted: 03/13/2025] [Indexed: 03/27/2025] Open
Abstract
Among the most common malignant tumors, hepatocellular carcinoma (HCC) is a primary liver cancer type that has a high mortality rate. HCC often presents insidiously, is prone to recurrence, and has limited treatment efficacy. Ferroptosis regulates tumorigenesis, progression, and metastasis, which is a novel form of iron-dependent cell death. Numerous studies suggest that HCC is sensitive to ferroptosis, indicating that targeted therapies aimed at inducing ferroptosis may represent a promising new approach to cancer treatment. This study aims to find genes associated with HCC and ferroptosis, as well as to screen for potential agents that may cause ferroptosis in HCC. Transcriptome and clinical sample data were obtained from the TCGA database to identify differentially expressed genes related to ferroptosis. Using various regression and survival analysis techniques, we developed a prognostic model based on four core genes and evaluated its predictive potential. Subsequently, we screened for potential therapeutic agents in the Connective Map (CMap) database, designated as compound Atorvastatin, based on differential genes from two risk groups and related to ferroptosis. Through experiments conducted in vivo and in vitro, we demonstrated that Atorvastatin can induce ferroptosis in HCC cells while inhibiting their growth and migration. In conclusion, this research targets ferroptosis therapy and provides new insights for improving the prediction and prevention of HCC.
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Affiliation(s)
| | | | | | | | | | | | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China; (L.W.); (X.H.); (Y.S.); (J.C.); (Y.C.); (Z.Z.)
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Noh JK, Lee MK, Lee Y, Bae M, Min S, Kong M, Lee JW, Kim SI, Lee YC, Ko S, Woo SR, Eun Y. Targeting ferroptosis for improved radiotherapy outcomes in HPV-negative head and neck squamous cell carcinoma. Mol Oncol 2025; 19:540-557. [PMID: 39297393 PMCID: PMC11792990 DOI: 10.1002/1878-0261.13720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 06/16/2024] [Accepted: 08/01/2024] [Indexed: 02/05/2025] Open
Abstract
To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV-negative HNSCC patients who underwent RT. This ferroptosis-related gene signature (FRGS) was a significant predictor of overall survival and recurrence-free survival in HPV-negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance-associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV-negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT-induced cell death.
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Affiliation(s)
- Joo Kyung Noh
- Department of Biomedical Science and Technology, Graduate SchoolKyung Hee UniversitySeoulKorea
| | - Min Kyeong Lee
- Department of Biomedical Science and Technology, Graduate SchoolKyung Hee UniversitySeoulKorea
| | - Yeonseo Lee
- Department of Biomedical Science and Technology, Graduate SchoolKyung Hee UniversitySeoulKorea
| | - Minji Bae
- Department of Biomedical Science and Technology, Graduate SchoolKyung Hee UniversitySeoulKorea
| | - Soonki Min
- Department of Radiation OncologyKyung Hee University School of Medicine, Kyung Hee University Medical CenterSeoulKorea
| | - Moonkyoo Kong
- Department of Radiation OncologyKyung Hee University School of Medicine, Kyung Hee University Medical CenterSeoulKorea
| | - Jung Woo Lee
- Department of Oral and Maxillofacial Surgery, School of DentistryKyung Hee UniversitySeoulKorea
| | - Su Il Kim
- Department of Otolaryngology‐Head and Neck SurgeryKyung Hee University School of Medicine, Kyung Hee University Medical CenterSeoulKorea
| | - Young Chan Lee
- Department of Otolaryngology‐Head and Neck SurgeryKyung Hee University School of Medicine, Kyung Hee University Medical CenterSeoulKorea
| | - Seong‐Gyu Ko
- Department of Preventive Medicine, College of Korean MedicineKyung Hee UniversitySeoulKorea
| | - Seon Rang Woo
- Department of Otolaryngology‐Head and Neck SurgeryKyung Hee University School of Medicine, Kyung Hee University Medical CenterSeoulKorea
| | - Young‐Gyu Eun
- Department of Biomedical Science and Technology, Graduate SchoolKyung Hee UniversitySeoulKorea
- Department of Otolaryngology‐Head and Neck SurgeryKyung Hee University School of Medicine, Kyung Hee University Medical CenterSeoulKorea
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:28-36. [DOI: 10.11569/wcjd.v33.i1.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/25/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:34-42. [DOI: 10.11569/wcjd.v33.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Xu Q, Liu X, Chen Z, Guo C, Lu P, Zhang S, Wang X, Shen J. Combination decoction of Astragalus mongholicus and Salvia miltiorrhiza mitigates pressure-overload cardiac dysfunction by inhibiting multiple ferroptosis pathways. Front Pharmacol 2024; 15:1447546. [PMID: 39737072 PMCID: PMC11683366 DOI: 10.3389/fphar.2024.1447546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/25/2024] [Indexed: 01/01/2025] Open
Abstract
Background Astragalus mongholicus (AM) and Salvia miltiorrhiza (SM) are commonly used in traditional Chinese medicine to treat heart failure (HF). Ferroptosis has been studied as a key factor in the occurrence of HF. It remains unclear whether the combined use of AM and SM can effectively improve HF and the underlying mechanisms. Objective This study aims to explore whether the combined use of AM and SM can improve HF by inhibiting ferroptosis. It also examines the roles and interactions of the pathways associated with GPX4, FSP1, and DHODH. Methods In vitro experiments used angiotensin II-induced (4 μM for 48 h) hypertrophic H9c2 cells, while in vivo studies employed a rat model of transverse aortic constriction-induced (to 1 mm for 8 weeks) HF. Interventions included decoctions of AM and SM (for animal experiments) and medicated serum (for cell experiments), along with specific pathway inhibitors such as erastin, FSP1 inhibitor and brequinar. Subsequently, various molecular biology methods were used to measure the protein levels of GPX4, FSP1, and DHODH, as well as each sample group's ferroptosis-related and HF-related indicators, to elucidate the underlying mechanisms. Results The combined use of AM and SM can effectively restore the levels of GPX4, FSP1, and DHODH that are reduced after HF, as well as improve indicators related to ferroptosis and HF. When GPX4, FSP1, or DHODH is inhibited, the ferroptosis-inhibiting effect and the ability of AM and SM to improve HF are both weakened. When two of the three proteins are inhibited, the protective effect of HDC is strongest when GPX4 is retained, followed by FSP1, and weakest when DHODH is retained. Conclusion This study confirms that the combined use of AM and SM inhibits ferroptosis and alleviates HF by increasing GPX4, FSP1, and DHODH levels. It shows that the protective effect is strongest through GPX4, followed by FSP1, and weakest through DHODH. These findings provide new insights into the therapeutic mechanisms of this combination of botanical drugs.
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Affiliation(s)
- Qiyao Xu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xuan Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Zhaoyang Chen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Can Guo
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Pengyu Lu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Sujie Zhang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xindong Wang
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jianping Shen
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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Zhao Y, Zheng G, Yang S, Liu S, Wu Y, Miao Y, Liang Z, Hua Y, Zhang J, Shi J, Li D, Cheng Y, Zhang Y, Chen Y, Fan G, Ma C. The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination. Br J Pharmacol 2024; 181:4822-4844. [PMID: 39228119 DOI: 10.1111/bph.17311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 06/04/2024] [Accepted: 06/23/2024] [Indexed: 09/05/2024] Open
Abstract
BACKGROUND AND PURPOSE Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (Panax notoginseng saponins), containing the main active ingredients of Panax notoginseng, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). EXPERIMENTAL APPROACH The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE-/- mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2-/- macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2-/- mice treated with high-fat diet (HFD) and AAV-PCSK9. KEY RESULTS PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. CONCLUSION AND IMPLICATIONS PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.
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Affiliation(s)
- Yun Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Guobin Zheng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Shu Yang
- Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Shangjing Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yifan Wu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yaodong Miao
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhen Liang
- Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Yunqing Hua
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jing Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jia Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Dan Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yanfei Cheng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yunsha Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yuanli Chen
- Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Zhang J, Wang S, Sun Q, Zhang J, Shi X, Yao M, Chen J, Huang Q, Zhang G, Huang Q, Ai K, Bai Y. Peroxynitrite-Free Nitric Oxide-Embedded Nanoparticles Maintain Nitric Oxide Homeostasis for Effective Revascularization of Myocardial Infarcts. ACS NANO 2024; 18:32650-32671. [PMID: 39545833 DOI: 10.1021/acsnano.4c10118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Revascularization is crucial for treating myocardial infarction (MI). Nitric oxide (NO), at an appropriate concentration, is recognized as an ideal and potent pro-angiogenic factor. However, the application of NO in the treatment of MI is limited. Improper NO supplementation is harmful to revascularization because NO is converted into harmful peroxynitrite (ONOO-) in MI tissues with high reactive oxygen species (ROS) levels. We overcome these obstacles by embedding biliverdin and NO into Prussian blue (PB) nanolattices to obtain an ONOO--free NO-embedded nanomedicine (OFEN). Unlike previous NO donors, OFEN provides NO stably and spontaneously for a longer time (>7 days), which makes it possible to maintain a stable concentration of NO, suitable for angiogenesis, through dose optimization. More importantly, based on the synergy between PB and biliverdin, OFEN converts ROS into beneficial O2 and inhibits the production of ONOO- from the source. OFEN specifically targets MI tissues and achieves sustained and stable NO delivery at the MI site. OFEN effectively promotes revascularization in the MI tissue, significantly reduces myocardial death and fibrosis, and ultimately promotes the complete recovery of cardiac function. Our strategy provides a promising approach for the treatment of myocardial and other ischemic diseases.
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Affiliation(s)
- Jiaxiong Zhang
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Shuya Wang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, PR China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, PR China
| | - Quan Sun
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Jian Zhang
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Xiaojing Shi
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, PR China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, PR China
| | - Meilian Yao
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Jing Chen
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Qiong Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Guogang Zhang
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410000, PR China
| | - Qun Huang
- Department of Child Health Care, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, PR China
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, PR China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, PR China
| | - Yongping Bai
- Department of Geriatric Medicine, Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
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Ge Y, Jiang L, Yang C, Dong Q, Tang C, Xu Y, Zhong X. Interactions between tumor-associated macrophages and regulated cell death: therapeutic implications in immuno-oncology. Front Oncol 2024; 14:1449696. [PMID: 39575419 PMCID: PMC11578871 DOI: 10.3389/fonc.2024.1449696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 10/21/2024] [Indexed: 11/24/2024] Open
Abstract
Tumor-associated macrophages (TAMs) play a pivotal role in sculpting the tumor microenvironment and influencing cancer progression, particularly through their interactions with various forms of regulated cell death (RCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis. This review examines the interplay between TAMs and these RCD pathways, exploring the mechanisms through which they interact to promote tumor growth and advancement. We examine the underlying mechanisms of these intricate interactions, emphasizing their importance in cancer progression and treatment. Moreover, we present potential therapeutic strategies for targeting TAMs and manipulating RCD to enhance anti-tumor responses. These strategies encompass reprogramming TAMs, inhibiting their recruitment, and selectively eliminating them to enhance anti-tumor functions, alongside modulating RCD pathways to amplify immune responses. These insights offer a novel perspective on tumor biology and provide a foundation for the development of more efficacious cancer therapies.
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Affiliation(s)
- Yifei Ge
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lixue Jiang
- Department of Breast Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Chengru Yang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qingfu Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Chengwu Tang
- Department of Hepatopancreatobiliary Surgery, Huzhou Key Laboratory of Translational Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- Department of Hepatopancreatobiliary Surgery, Huzhou Key Laboratory of Translational Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, China
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xiangyu Zhong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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9
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Li X, Tian M, Yu L, Qian J, Yang J, Wang X, Lu C, Xiao C, Liu Y. The role of ferroptosis resistance in lymph-associated tumour metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189200. [PMID: 39426689 DOI: 10.1016/j.bbcan.2024.189200] [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: 05/30/2024] [Revised: 10/11/2024] [Accepted: 10/13/2024] [Indexed: 10/21/2024]
Abstract
Tumour metastasis is a crucial factor in determining clinically challenging tumours. In this respect, the lymphatic system may act as potential entry portals for tumour metastasis, whilst, clinical detection of tumour-infiltrated lymph nodes also indicates poorer prognosis and higher metastatic risk. Whether tumour cells gain ferroptosis resistance in lymph that make them exhibit a stronger propensity for lymphatic dissemination compared to hematogenous spread might be a breakthrough for elucidating lymph-associated tumour metastasis. This review discusses how the lymphatic system endows tumour cells with ferroptosis resistance character, which makes them more propensity for lymph node pre-metastasis and distant metastasis through lymphatic circulation. Comprehensively considering the distinct structure and property of lymph and the unique metabolic characteristics of tumours, all of the lymphatic vessels, intestinal lymph and lymph nodes collectively manipulate an intricate interaction with the hematogenous system and afford substances exchange with tumour cells and extracellular vesicles, upon which make a ferroptosis resistant microenvironment for subsequent metastasis in distant organs and lymph nodes.
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Affiliation(s)
- Xiaoyu Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Meng Tian
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Liuchunyang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - JinXiu Qian
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jue Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiangpeng Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China.
| | - Yuanyan Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
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10
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He C, Li Q, Wu W, Liu K, Li X, Zheng H, Lai Y. Ferroptosis-associated genes and compounds in renal cell carcinoma. Front Immunol 2024; 15:1473203. [PMID: 39399506 PMCID: PMC11466770 DOI: 10.3389/fimmu.2024.1473203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/09/2024] [Indexed: 10/15/2024] Open
Abstract
As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxia-inducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHL-deficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis.
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Affiliation(s)
- Chengwu He
- Department of Urology, Shenzhen Shockwave Lithotripsy Research Institute, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Qingyi Li
- Department of Urology, Shenzhen Shockwave Lithotripsy Research Institute, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Weijia Wu
- Department of Urology, Shenzhen Shockwave Lithotripsy Research Institute, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Ke Liu
- Department of Urology, Shenzhen Shockwave Lithotripsy Research Institute, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Xingwen Li
- Tibet Future Biomedicine Company Limited, Golmud, Qinghai, China
| | - Hanxiong Zheng
- Department of Urology, Shenzhen Shockwave Lithotripsy Research Institute, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yongchang Lai
- Department of Pharmaceutical Management, School of Medical Business, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China
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11
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Jin X, Jin W, Tong L, Zhao J, Zhang L, Lin N. Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer. Acta Pharm Sin B 2024; 14:2815-2853. [PMID: 39027232 PMCID: PMC11252466 DOI: 10.1016/j.apsb.2024.04.020] [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: 12/27/2023] [Revised: 02/29/2024] [Accepted: 03/18/2024] [Indexed: 07/20/2024] Open
Abstract
Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.
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Affiliation(s)
- Xin Jin
- Department of Ultrasound, Department of Medical Oncology and Department of Hematology, the First Hospital of China Medical University, China Medical University, Shenyang 110001, China
| | - Wenke Jin
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Linlin Tong
- Department of Ultrasound, Department of Medical Oncology and Department of Hematology, the First Hospital of China Medical University, China Medical University, Shenyang 110001, China
| | - Jia Zhao
- Department of Ultrasound, Department of Medical Oncology and Department of Hematology, the First Hospital of China Medical University, China Medical University, Shenyang 110001, China
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Na Lin
- Department of Ultrasound, Department of Medical Oncology and Department of Hematology, the First Hospital of China Medical University, China Medical University, Shenyang 110001, China
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12
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Kasperova BJ, Mraz M, Svoboda P, Hlavacek D, Kratochvilova H, Modos I, Vrzackova N, Ivak P, Janovska P, Kobets T, Mahrik J, Riecan M, Steiner Mrazova L, Stranecky V, Netuka I, Cajka T, Kuda O, Melenovsky V, Stemberkova Hubackova S, Haluzik M. Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure. Cardiovasc Diabetol 2024; 23:223. [PMID: 38943140 PMCID: PMC11214218 DOI: 10.1186/s12933-024-02298-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 06/05/2024] [Indexed: 07/01/2024] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.
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Affiliation(s)
- Barbora Judita Kasperova
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
- First Faculty of Medicine, Charles University in Prague, Katerinska 1660/32, 121 08, Prague, Czech Republic
| | - Milos Mraz
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 499/2, 128 08, Prague, Czech Republic
| | - Petr Svoboda
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
- Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic
| | - Daniel Hlavacek
- Department of Cardiac Surgery, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
- Third Faculty of Medicine, Charles University in Prague, Ruska 87, 100 00, Prague, Czech Republic
| | - Helena Kratochvilova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Istvan Modos
- Department of Informatics, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Nikola Vrzackova
- Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technicka 5, 166 28, Prague, Czech Republic
| | - Peter Ivak
- Department of Cardiac Surgery, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
- Third Faculty of Medicine, Charles University in Prague, Ruska 87, 100 00, Prague, Czech Republic
| | - Petra Janovska
- Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic
| | - Tatyana Kobets
- Department of Metabolomics, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic
| | - Jakub Mahrik
- First Faculty of Medicine, Charles University in Prague, Katerinska 1660/32, 121 08, Prague, Czech Republic
- Department of Cardiac Anesthesia, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Martin Riecan
- Department of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic
| | - Lenka Steiner Mrazova
- Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic
- Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 455/2, 128 08, Prague, Czech Republic
| | - Viktor Stranecky
- Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Ke Karlovu 455/2, 128 08, Prague, Czech Republic
| | - Ivan Netuka
- Department of Cardiac Surgery, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Tomas Cajka
- Department of Metabolomics, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic
| | - Ondrej Kuda
- Department of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 142 00, Prague, Czech Republic
| | - Vojtech Melenovsky
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Sona Stemberkova Hubackova
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic.
| | - Martin Haluzik
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21, Prague, Czech Republic.
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 499/2, 128 08, Prague, Czech Republic.
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13
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Shu YJ, Lao B, Qiu YY. Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer. World J Gastrointest Oncol 2024; 16:2335-2349. [PMID: 38994128 PMCID: PMC11236230 DOI: 10.4251/wjgo.v16.i6.2335] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/06/2024] [Accepted: 04/11/2024] [Indexed: 06/13/2024] Open
Abstract
As a highly aggressive tumor, the pathophysiological mechanism of primary liver cancer has attracted much attention. In recent years, factors such as ferroptosis regulation, lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer, providing a new perspective for understanding the development of liver cancer. Ferroptosis regulation, lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer. The regulation of ferroptosis is involved in apoptosis and necrosis, affecting cell survival and death. Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells. Metabolic abnormalities, especially the disorders of glucose and lipid metabolism, directly affect the proliferation and growth of liver cancer cells. Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes. The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer, and reduce the risk of disease by adjusting the metabolic process. This review focuses on the key roles of ferroptosis regulation, lipid peroxidation and metabolic abnormalities in this process.
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Affiliation(s)
- Yu-Jie Shu
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Bo Lao
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
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14
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Jiang Y, Glandorff C, Sun M. GSH and Ferroptosis: Side-by-Side Partners in the Fight against Tumors. Antioxidants (Basel) 2024; 13:697. [PMID: 38929136 PMCID: PMC11201279 DOI: 10.3390/antiox13060697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/26/2024] [Accepted: 06/01/2024] [Indexed: 06/28/2024] Open
Abstract
Glutathione (GSH), a prominent antioxidant in organisms, exhibits diverse biological functions and is crucial in safeguarding cells against oxidative harm and upholding a stable redox milieu. The metabolism of GSH is implicated in numerous diseases, particularly in the progression of malignant tumors. Consequently, therapeutic strategies targeting the regulation of GSH synthesis and metabolism to modulate GSH levels represent a promising avenue for future research. This study aimed to elucidate the intricate relationship between GSH metabolism and ferroptosis, highlighting how modulation of GSH metabolism can impact cellular susceptibility to ferroptosis and consequently influence the development of tumors and other diseases. The paper provides a comprehensive overview of the physiological functions of GSH, including its structural characteristics, physicochemical properties, sources, and metabolic pathways, as well as investigate the molecular mechanisms underlying GSH regulation of ferroptosis and potential therapeutic interventions. Unraveling the biological role of GSH holds promise for individuals afflicted with tumors.
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Affiliation(s)
- Yulang Jiang
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (C.G.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Christian Glandorff
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (C.G.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- University Clinic of Hamburg at the HanseMerkur Center of TCM, 20251 Hamburg, Germany
| | - Mingyu Sun
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (C.G.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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15
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Yano M, Nishino M, Kawanami S, Ukita K, Kawamura A, Yasumoto K, Tsuda M, Okamoto N, Matsunaga‐Lee Y, Egami Y, Yamada T, Yasumura Y, Seo M, Hayashi T, Nakagawa A, Nakagawa Y, Tamaki S, Sotomi Y, Nakatani D, Hikoso S, Sakata Y. Low-density lipoprotein cholesterol, erythrocyte, and platelet in heart failure with preserved ejection fraction. ESC Heart Fail 2024; 11:1758-1766. [PMID: 38454876 PMCID: PMC11098649 DOI: 10.1002/ehf2.14734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 03/09/2024] Open
Abstract
AIMS Low-density lipoprotein cholesterol (LDL-C), anaemia and low platelets have been associated with worse clinical outcomes in heart failure patients. We investigated the relationship between the combination of these three components and clinical outcome in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS We examined the data of 1021 patients with HFpEF hospitalized with acute decompensated heart failure (HF) from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. The enrolled patients were classified into four groups by an LEP (LDL-C, Erythrocyte, and Platelet) score of 0 to 3 points, with 1 point each for LDL-C, erythrocyte and platelet values less than the cut-off values as calculated by receiver operating characteristic curve analysis. The endpoint, a composite of all-cause death and HF readmission, was evaluated among the four groups. Median follow-up duration was 579 [300, 978] days. Risk of the composite endpoint significantly differed among the four groups (P < 0.001). Kaplan-Meier analysis showed that the groups with an LEP score of 2 had higher risk of the composite endpoint than those with an LEP score of 0 or 1 (P < 0.001, and P = 0.013, respectively), while those with an LEP score of 3 had higher risk than those with an LEP score of 0, 1 or 2 (P < 0.001, P < 0.001 and P = 0.020, respectively). Cox proportional hazards analysis showed that an LEP score of 3 was significantly associated with the composite endpoint (P = 0.030). Kaplan-Meier analysis showed that risk of the composite of all-cause death and HF readmission was significantly higher in low LDL values (less than the cut-off values as calculated by receiver operating characteristic curve analysis) patients with statin use than in those without statin use (log rank P = 0.002). CONCLUSIONS LEP score, which comprehensively reflects extra-cardiac co-morbidities, is significantly associated with clinical outcomes in HFpEF patients.
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Affiliation(s)
| | | | | | - Kohei Ukita
- Division of CardiologyOsaka Rosai HospitalOsakaJapan
| | | | - Koji Yasumoto
- Division of CardiologyOsaka Rosai HospitalOsakaJapan
| | - Masaki Tsuda
- Division of CardiologyOsaka Rosai HospitalOsakaJapan
| | | | | | | | - Takahisa Yamada
- Division of CardiologyOsaka General Medical CenterOsakaJapan
| | | | - Masahiro Seo
- Division of CardiologyOsaka General Medical CenterOsakaJapan
| | | | - Akito Nakagawa
- Division of CardiologyAmagasaki Chuo HospitalAmagasakiJapan
- Department of Medical InformaticsOsaka University Graduate School of MedicineOsakaJapan
| | - Yusuke Nakagawa
- Division of CardiologyKawanishi City Medical CenterKawanishiJapan
| | - Shunsuke Tamaki
- Department of Cardiology, Pulmonology, Hypertension, NephrologyEhime University Graduate School of MedicineToonJapan
- Department of CardiologyRinku General Medical CenterOsakaJapan
| | - Yohei Sotomi
- Department of Cardiovascular MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Daisaku Nakatani
- Department of Cardiovascular MedicineOsaka University Graduate School of MedicineOsakaJapan
| | - Shungo Hikoso
- Department of Cardiovascular MedicineOsaka University Graduate School of MedicineOsakaJapan
- Department of Cardiovascular MedicineNara Medical UniversityNaraJapan
| | - Yasushi Sakata
- Department of Cardiovascular MedicineOsaka University Graduate School of MedicineOsakaJapan
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16
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Zhang S, Ren X, Zhang B, Lan T, Liu B. A Systematic Review of Statins for the Treatment of Nonalcoholic Steatohepatitis: Safety, Efficacy, and Mechanism of Action. Molecules 2024; 29:1859. [PMID: 38675679 PMCID: PMC11052408 DOI: 10.3390/molecules29081859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver component of a cluster of conditions, while its subtype, nonalcoholic steatohepatitis (NASH), emerges as a potentially progressive liver disorder that harbors the risk of evolving into cirrhosis and culminating in hepatocellular carcinoma (HCC). NASH and cardiovascular disease (CVD) have common risk factors, but compared to liver-related causes, the most common cause of death in NASH patients is CVD. Within the pharmacological armamentarium, statins, celebrated for their lipid-modulating prowess, have now garnered attention for their expansive therapeutic potential in NASH. Evidence from a plethora of studies suggests that statins not only manifest anti-inflammatory and antifibrotic properties but also impart a multifaceted beneficial impact on hepatic health. In this review, we used "statin", "NAFLD", "NASH", and "CVD" as the major keywords and conducted a literature search using the PubMed and Web of Science databases to determine the safety and efficacy of statins in patients and animals with NASH and NAFLD, and the mechanism of statin therapy for NASH. Simultaneously, we reviewed the important role of the intestinal microbiota in statin therapy for NASH, as it is hoped that statins will provide new insights into modulating the harmful inflammatory microbiota in the gut and reducing systemic inflammation in NASH patients.
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Affiliation(s)
- Shiqin Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.Z.); (X.R.); (B.Z.)
| | - Xiaoling Ren
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.Z.); (X.R.); (B.Z.)
| | - Bingzheng Zhang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.Z.); (X.R.); (B.Z.)
| | - Tian Lan
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.Z.); (X.R.); (B.Z.)
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Bing Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; (S.Z.); (X.R.); (B.Z.)
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17
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Firouzjaei AA, Mahmoudi A, Almahmeed W, Teng Y, Kesharwani P, Sahebkar A. Identification and analysis of the molecular targets of statins in colorectal cancer. Pathol Res Pract 2024; 256:155258. [PMID: 38522123 DOI: 10.1016/j.prp.2024.155258] [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: 01/16/2024] [Revised: 02/05/2024] [Accepted: 03/08/2024] [Indexed: 03/26/2024]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world. According to several types of research, statins may impact the development and treatment of CRC. This work aimed to use bioinformatics to discover the relationship between statin targets and differentially expressed genes (DEGs) in CRC patients and determine the possible molecular effect of statins on CRC suppression. We used CRC datasets from the GEO database to select CRC-related DEGs. DGIdb and STITCH databases were used to identify gene targets of subtypes of statin. Further, we identified the statin target of CRC DEGs hub genes by using a Venn diagram of CRC DEGs and statin targets. Funrich and enrichr databases were carried out for the KEGG pathway and gene ontology (GO) enrichment analysis, respectively. GSE74604 and GSE10950 were used to identify CRC DEGs. After analyzing datasets,1370 genes were identified as CRC DEGs, and 345 targets were found for statins. We found that 35 genes are CRC DEGs statin targets. We found that statin targets in CRC were enriched in the receptor and metallopeptidase activity for molecular function, cytoplasm and plasma membrane for cellular component, signal transduction, and cell communication for biological process genes were substantially enriched based on FunRich enrichment. Analysis of the KEGG pathways revealed that the overexpressed DEGs were enriched in the IL-17, PPAR, and Toll-like receptor signaling pathways. Finally, CCNB1, DNMT1, AURKB, RAC1, PPARGC1A, CDKN1A, CAV1, IL1B, and HSPD1 were identified as hub CRC DEGs statin targets. The genetic and molecular aspects of our findings reveal that statins might have a therapeutic effect on CRC.
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Affiliation(s)
- Ali Ahmadizad Firouzjaei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Mahmoudi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Amirhossein Sahebkar
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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18
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Yang W, Wang Y, Li H, Liao F, Peng Y, Lu A, Tan L, Qu H, Long L, Fu C. Enhanced TfR1 Recognition of Myocardial Injury after Acute Myocardial Infarction with Cardiac Fibrosis via Pre-Degrading Excess Fibrotic Collagen. BIOLOGY 2024; 13:213. [PMID: 38666825 PMCID: PMC11048469 DOI: 10.3390/biology13040213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 04/28/2024]
Abstract
The fibrosis process after myocardial infarction (MI) results in a decline in cardiac function due to fibrotic collagen deposition and contrast agents' metabolic disorders, posing a significant challenge to conventional imaging strategies in making heart damage clear in the fibrosis microenvironment. To address this issue, we developed an imaging strategy. Specifically, we pretreated myocardial fibrotic collagen with collagenase I combined with human serum albumin (HSA-C) and subsequently visualized the site of cardiac injury by near-infrared (NIR) fluorescence imaging using an optical contrast agent (CI, CRT-indocyanine green) targeting transferrin receptor 1 peptides (CRT). The key point of this strategy is that pretreatment with HSA-C can reduce background signal interference in the fibrotic tissue while enhancing CI uptake at the heart lesion site, making the boundary between the injured heart tissue and the normal myocardium clearer. Our results showed that compared to that in the untargeted group, the normalized fluorescence intensity of cardiac damage detected by NIR in the targeted group increased 1.28-fold. The normalized fluorescence intensity increased 1.21-fold in the pretreatment group of the targeted groups. These data demonstrate the feasibility of applying pretreated fibrotic collagen and NIR contrast agents targeting TfR1 to identify ferroptosis at sites of cardiac injury, and its clinical value in the management of patients with MI needs further study.
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Affiliation(s)
- Wenwen Yang
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Yueqi Wang
- CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Hongzheng Li
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Feifei Liao
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yuxuan Peng
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Aimei Lu
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Ling Tan
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Hua Qu
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Linzi Long
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Changgeng Fu
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
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19
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Jiang Y, Yu Y, Pan Z, Glandorff C, Sun M. Ferroptosis: a new hunter of hepatocellular carcinoma. Cell Death Discov 2024; 10:136. [PMID: 38480712 PMCID: PMC10937674 DOI: 10.1038/s41420-024-01863-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/06/2024] [Accepted: 02/12/2024] [Indexed: 03/17/2024] Open
Abstract
Ferroptosis is an iron ion-dependent, regulatory cell death modality driven by intracellular lipid peroxidation that plays a key role in the development of HCC. Studies have shown that various clinical agents (e.g., sorafenib) have ferroptosis inducer-like effects and can exert therapeutic effects by modulating different key factors in the ferroptosis pathway. This implies that targeting tumor cell ferroptosis may be a very promising strategy for tumor therapy. In this paper, we summarize the prerequisites and defense systems for the occurrence of ferroptosis and the regulatory targets of drug-mediated ferroptosis action in HCC, the differences and connections between ferroptosis and other programmed cell deaths. We aim to summarize the theoretical basis, classical inducers of ferroptosis and research progress of ferroptosis in HCC cells, clued to the treatment of HCC by regulating ferroptosis network. Further investigation of the specific mechanisms of ferroptosis and the development of hepatocellular carcinoma and interventions at different stages of hepatocellular carcinoma will help us to deepen our understanding of hepatocellular carcinoma, with a view to providing new and more precise preventive as well as therapeutic measures for patients.
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Affiliation(s)
- Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yongxin Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ziyang Pan
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Christian Glandorff
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- University Clinic of Hamburg at the HanseMerkur Center of TCM, Hamburg, Germany
| | - Mingyu Sun
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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20
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Zhou Q, Meng Y, Li D, Yao L, Le J, Liu Y, Sun Y, Zeng F, Chen X, Deng G. Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies. Signal Transduct Target Ther 2024; 9:55. [PMID: 38453898 PMCID: PMC10920854 DOI: 10.1038/s41392-024-01769-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/21/2024] [Accepted: 02/03/2024] [Indexed: 03/09/2024] Open
Abstract
Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation of iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in the biological processes of tumors. Intriguingly, mesenchymal and dedifferentiated cancer cells, which are usually resistant to apoptosis and traditional therapies, are exquisitely vulnerable to ferroptosis, further underscoring its potential as a treatment approach for cancers, especially for refractory cancers. However, the impact of ferroptosis on cancer extends beyond its direct cytotoxic effect on tumor cells. Ferroptosis induction not only inhibits cancer but also promotes cancer development due to its potential negative impact on anticancer immunity. Thus, a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from the laboratory to clinical applications. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms, biological functions, regulatory pathways, and interactions with the tumor microenvironment. We also summarize the potential applications of ferroptosis induction in immunotherapy, radiotherapy, and systemic therapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis markers, the current challenges and future directions of ferroptosis in the treatment of cancer.
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Affiliation(s)
- Qian Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Yu Meng
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Daishi Li
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Lei Yao
- Department of General Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Jiayuan Le
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Yihuang Liu
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- Furong Laboratory, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha, 410008, Hunan Province, China.
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21
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Hou K, Liu L, Fang ZH, Zong WX, Sun D, Guo Z, Cao L. The role of ferroptosis in cardio-oncology. Arch Toxicol 2024; 98:709-734. [PMID: 38182913 DOI: 10.1007/s00204-023-03665-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 12/11/2023] [Indexed: 01/07/2024]
Abstract
With the rapid development of new generations of antitumor therapies, the average survival time of cancer patients is expected to be continuously prolonged. However, these therapies often lead to cardiotoxicity, resulting in a growing number of tumor survivors with cardiovascular disease. Therefore, a new interdisciplinary subspecialty called "cardio-oncology" has emerged, aiming to detect and treat cardiovascular diseases associated with tumors and antitumor therapies. Recent studies have highlighted the role of ferroptosis in both cardiovascular and neoplastic diseases. The balance between intracellular oxidative stress and antioxidant defense is crucial in regulating ferroptosis. Tumor cells can evade ferroptosis by upregulating multiple antioxidant defense pathways, while many antitumor therapies rely on downregulating antioxidant defense and promoting ferroptosis in cancer cells. Unfortunately, these ferroptosis-inducing antitumor therapies often lack tissue specificity and can also cause injury to the heart, resulting in ferroptosis-induced cardiotoxicity. A range of cardioprotective agents exert cardioprotective effects by inhibiting ferroptosis. However, these cardioprotective agents might diminish the efficacy of antitumor treatment due to their antiferroptotic effects. Most current research on ferroptosis only focuses on either tumor treatment or heart protection but rarely considers both in concert. Therefore, further research is needed to study how to protect the heart during antitumor therapies by regulating ferroptosis. In this review, we summarized the role of ferroptosis in the treatment of neoplastic diseases and cardiovascular diseases and also attempted to propose further research directions for ferroptosis in the field of cardio-oncology.
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Affiliation(s)
- Kai Hou
- Tianjin Medical University, Tianjin, 300070, China.
- Tianjin Chest Hospital, Tianjin, 300222, China.
- Chest Hospital, Tianjin University, Tianjin, 300222, China.
- Pu'er People's Hospital, Yunnan, 665000, China.
| | - Lin Liu
- Institute of Natural Sciences, MOE-LSC, School of Mathematical Sciences, CMA-Shanghai, SJTU-Yale Joint Center for Biostatistics and Data Science, Shanghai Jiao Tong University, Shanghai, 200240, China
| | | | - Wei-Xing Zong
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, 08854, USA
| | - Daqiang Sun
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Chest Hospital, Tianjin, 300222, China
- Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Zhigang Guo
- Tianjin Medical University, Tianjin, 300070, China
- Tianjin Chest Hospital, Tianjin, 300222, China
- Chest Hospital, Tianjin University, Tianjin, 300222, China
| | - Lu Cao
- Tianjin Chest Hospital, Tianjin, 300222, China.
- Chest Hospital, Tianjin University, Tianjin, 300222, China.
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22
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Gu Y, Cui M, Wang W, Zhang J, Wang H, Zheng C, Lei L, Ji M, Chen W, Xu Y, Wang P. Visualization of the Ferroptosis in Atherosclerotic Plaques with Nanoprobe Engineered by Macrophage Cell Membranes. Anal Chem 2024; 96:281-291. [PMID: 38153251 DOI: 10.1021/acs.analchem.3c03999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Atherosclerosis (AS) is the root cause of cardiovascular diseases. Ferroptosis is characterized by highly iron-dependent lipid peroxidation and has been reported to play an important role in the pathogenesis of AS. Visualization of the ferroptosis process in atherosclerotic plaques is of great importance for diagnosing and treating AS. In this work, the rationally designed fluorescent probe FAS1 exhibited excellent advantages including large Stokes shift, sensitivity to environmental viscosity, good photostability, and improved water solubility. It also could co-locate with commercial lipid droplets (LDs) probes (BODIPY 493/503) well in RAW264.7 cells treated by the ferroptosis inducer. After self-assembly into nanoparticles and then encapsulation with macrophage membranes, the engineered FAS1@MM NPs could successfully target the atherosclerotic plaques in Western diet-induced apolipoprotein E knockout (ApoE-/-) mice and reveal the association of ferroptosis with AS through fluorescence imaging in vivo. This study may provide additional insights into the roles of ferroptosis in the diagnosis and treatment of AS.
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Affiliation(s)
- Yinhui Gu
- Department of Nuclear Medicine & Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610044, China
- Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Mengyuan Cui
- School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Weizhi Wang
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC), Beijing 100050, China
| | - Jiaqi Zhang
- Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Huizhe Wang
- Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
| | - Cheng Zheng
- Department of Nuclear Medicine & Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610044, China
| | - Lijuan Lei
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC), Beijing 100050, China
| | - Min Ji
- School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Wei Chen
- Department of Nuclear Medicine & Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610044, China
| | - Yanni Xu
- NHC Key Laboratory of Biotechnology of Antibiotics, National Center for New Microbial Drug Screening, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS&PUMC), Beijing 100050, China
| | - Peng Wang
- Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China
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23
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Zhou D, Lu P, Mo X, Yang B, Chen T, Yao Y, Xiong T, Yue L, Yang X. Ferroptosis and metabolic syndrome and complications: association, mechanism, and translational applications. Front Endocrinol (Lausanne) 2024; 14:1248934. [PMID: 38260171 PMCID: PMC10800994 DOI: 10.3389/fendo.2023.1248934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Metabolic syndrome is a medical condition characterized by several metabolic disorders in the body. Long-term metabolic disorders raise the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Therefore, it is essential to actively explore the aetiology of metabolic syndrome (MetS) and its comorbidities to provide effective treatment options. Ferroptosis is a new form of cell death that is characterized by iron overload, lipid peroxide accumulation, and decreased glutathione peroxidase 4(GPX4) activity, and it involves the pathological processes of a variety of diseases. Lipid deposition caused by lipid diseases and iron overload is significant in metabolic syndrome, providing the theoretical conditions for developing ferroptosis. Recent studies have found that the major molecules of ferroptosis are linked to common metabolic syndrome consequences, such as T2DM and atherosclerosis. In this review, we first discussed the mechanics of ferroptosis, the regulatory function of inducers and inhibitors of ferroptosis, and the significance of iron loading in MetS. Next, we summarized the role of ferroptosis in the pathogenesis of MetS, such as obesity, type 2 diabetes, and atherosclerosis. Finally, we discussed relevant ferroptosis-targeted therapies and raised some crucial issues of concern to provide directions for future Mets-related treatments and research.
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Affiliation(s)
- Dongmei Zhou
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Peipei Lu
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Xianglai Mo
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Bing Yang
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Ting Chen
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - You Yao
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Tian Xiong
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Lin Yue
- School of Nursing, Hunan University of Medicine, Huaihua, China
| | - Xi Yang
- Department of Endocrinology, Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, First Affiliated Hospital, Guangxi Medical University, Nanning, China
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24
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Wang Y, Sun Y, Wang F, Wang H, Hu J. Ferroptosis induction via targeting metabolic alterations in triple-negative breast cancer. Biomed Pharmacother 2023; 169:115866. [PMID: 37951026 DOI: 10.1016/j.biopha.2023.115866] [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: 09/13/2023] [Revised: 11/04/2023] [Accepted: 11/07/2023] [Indexed: 11/13/2023] Open
Abstract
Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, presents severe threats to women's health. Therefore, it is critical to find novel treatment approaches. Ferroptosis, a newly identified form of programmed cell death, is marked by the buildup of lipid reactive oxygen species (ROS) and high iron concentrations. According to previous studies, ferroptosis sensitivity can be controlled by a number of metabolic events in cells, such as amino acid metabolism, iron metabolism, and lipid metabolism. Given that TNBC tumors are rich in iron and lipids, inducing ferroptosis in these tumors is a potential approach for TNBC treatment. Notably, the metabolic adaptability of cancer cells allows them to coordinate an attack on one or more metabolic pathways to initiate ferroptosis, offering a novel perspective to improve the high drug resistance and clinical therapy of TNBC. However, a clear picture of ferroptosis in TNBC still needs to be completely revealed. In this review, we provide an overview of recent advancements regarding the connection between ferroptosis and amino acid, iron, and lipid metabolism in TNBC. We also discuss the probable significance of ferroptosis as an innovative target for chemotherapy, radiotherapy, immunotherapy, nanotherapy and natural product therapy in TNBC, highlighting its therapeutic potential and application prospects.
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Affiliation(s)
- Yaru Wang
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yue Sun
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Feiran Wang
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Hongyi Wang
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Jing Hu
- The Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
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25
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Peng W, Qian Y, Qi X. Efficacy of a novel glioma therapy based on ferroptosis induced by layered double hydroxide loaded with simvastatin. ENVIRONMENTAL RESEARCH 2023; 238:117112. [PMID: 37717807 DOI: 10.1016/j.envres.2023.117112] [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: 07/31/2023] [Revised: 09/04/2023] [Accepted: 09/09/2023] [Indexed: 09/19/2023]
Abstract
Glioma is the most common primary malignant tumor of the nervous system that starts in the glial cells. Its high invasiveness and recurrence pose major challenges to its effective treatment. Ferroptosis is a new type of programmed cell death characterized by intracellular iron overload and accumulation of lipid peroxides. Existing studies have demonstrated the efficacy of targeted ferroptosis therapy in the treatment of glioma. In this study, folic acid (FA)-modified layered double hydroxide loaded with simvastatin (SIM), a ferroptosis drug, was used to prepare a novel ferroptosis nanodrug (FA-LDH@SIM). The prepared nanodrug improved the therapeutic effect of SIM on glioma. Compared with free SIM, FA-LDH@SIM showed greater cytotoxicity, significantly inhibited glioma cell proliferation, and significantly inhibited glioma invasion and migration ability. Furthermore, SIM could induce changes in certain ferroptosis indicators, including increased intracellular LPO, ROS and MDA level, decreased GSH production, increased divalent iron level, and changes in mitochondrial morphology. Further experiments revealed that SIM induced ferroptosis in tumor cells by down-regulating HMGCR expression and inhibiting the mevalonate pathway to down-regulate GPX4 expression. In addition, the FA-LDH@SIM group significantly inhibited tumor growth after treatment in the animal glioma model. These results indicate that the FA-LDH@SIM nanodrug delivery system exhibits excellent anti-tumor effects both in vitro and in vivo, and is an effective method for the treatment of glioma.
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Affiliation(s)
- Wei Peng
- Medical Research Center, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, No. 568, Zhongxing Road, Shaoxing, 312000, Zhejiang, China.
| | - Yufeng Qian
- Department of Neurosurgery, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, No. 568, Zhongxing Road, Shaoxing 312000, Zhejiang, China.
| | - Xuchen Qi
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun East Road, Shangcheng District, Hangzhou 310000, Zhejiang, China; Department of Neurosurgery, Shaoxing People's Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, No. 568, Zhongxing Road, Shaoxing 312000, Zhejiang, China.
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