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Esmaeili A, Awasthi P, Tabaee S. Beyond immortality: Epstein-Barr virus and the intricate dance of programmed cell death in cancer development. Cancer Treat Res Commun 2025; 43:100880. [PMID: 39923321 DOI: 10.1016/j.ctarc.2025.100880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 02/11/2025]
Abstract
This comprehensive review delves into the intricate role of programmed cell death in Epstein-Barr virus (EBV)-associated malignancies, focusing on the sophisticated interplay between viral mechanisms and the host's immune response. The central objective is to unravel how EBV exerts control over cell death pathways such as apoptosis, ferroptosis, and autophagy, thereby fostering its persistence and oncogenic potential. By dissecting these mechanisms, the review seeks to identify therapeutic strategies that could disrupt EBV's manipulation of these pathways, enhancing immune recognition and opening new avenues for targeted treatment. A deeper understanding of the molecular underpinnings of EBV's influence on cell death not only enriches the field of viral oncology but also pinpoints targets for drug development. Furthermore, the insights gleaned from this review could catalyze the design of vaccines aimed at preventing EBV infection or curtailing its oncogenic impact. Innovatively, the review synthesizes recent discoveries on the multifaceted roles of non-coding RNAs and cellular signaling pathways in modulating cell death within the context of EBV infection. By consolidating current knowledge and identifying areas where understanding is lacking, it lays the groundwork for future research that could lead to significant advancements in vaccine development and therapeutic interventions for EBV-related cancers. This review underscores the critical necessity for ongoing investigation into the complex interplay between EBV and host cell death mechanisms, with the ultimate goal of enhancing patient outcomes in EBV-associated diseases.
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Affiliation(s)
- Arezoo Esmaeili
- Department of biology, Damghan Branch, Islamic Azad University, Damghan, Iran.
| | - Prankur Awasthi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, India
| | - Samira Tabaee
- Department of immunology, school of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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2
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Liu X, Tuerxun H, Zhao Y, Li Y, Wen S, Li X, Zhao Y. Crosstalk between ferroptosis and autophagy: broaden horizons of cancer therapy. J Transl Med 2025; 23:18. [PMID: 39762980 PMCID: PMC11702107 DOI: 10.1186/s12967-024-06059-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
Ferroptosis and autophagy are two main forms of regulated cell death (RCD). Ferroptosis is a newly identified RCD driven by iron accumulation and lipid peroxidation. Autophagy is a self-degradation system through membrane rearrangement. Autophagy regulates the metabolic balance between synthesis, degradation and reutilization of cellular substances to maintain intracellular homeostasis. Numerous studies have demonstrated that both ferroptosis and autophagy play important roles in cancer pathogenesis and cancer therapy. We also found that there are intricate connections between ferroptosis and autophagy. In this article, we tried to clarify how different kinds of autophagy participate in the process of ferroptosis and sort out the common regulatory pathways between ferroptosis and autophagy in cancer. By exploring the complex crosstalk between ferroptosis and autophagy, we hope to broaden horizons of cancer therapy.
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Affiliation(s)
- Xingyu Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Halahati Tuerxun
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yixin Zhao
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yawen Li
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Shuhui Wen
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xi Li
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yuguang Zhao
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China.
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3
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Liu P, Zhang Z, Chen Q. [Roles of ferroptosis in the development of diabetic nephropathy]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:708-714. [PMID: 39757741 PMCID: PMC11736350 DOI: 10.3724/zdxbyxb-2024-0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 10/28/2024] [Indexed: 01/07/2025]
Abstract
Diabetic nephropathy is a common microvascular complication of diabetes mellitus and one of the main causes of death in patients with diabetes mellitus. Ferroptosis is a newly discovered iron-dependent regulated cell death, which may contribute to the pathogenesis and development of diabetic nephropathy. Adenosine monophosphate-activated protein kinase (AMPK)-mediated ferroptosis-related signaling pathways can slow down the progression of diabetic nephropathy, but excessive activation of AMPK signaling pathway may induce cells to undergo autophagic death. Activation of the signaling pathway mediated by nuclear factor-erythroid 2-related factor (Nrf) 2 and heme oxygenase (HO)-1 can inhibit ferroptosis of cells and alleviate diabetic nephropathy. However, the regulatory effect of HO-1 on ferroptosis is bidirectional, and activation of HIF-1α/HO-1 pathway may lead to intracellular iron overload and ultimately promote ferroptosis. Transforming growth factor (TGF)-β1 mediated signaling pathways can accelerate lipid peroxidation by down-regulating the levels of SLC7A11/GSH/GPX4. The ferroptosis-related signaling pathways mediated by exosome lncRNAs/circRNAs/miRNAs are also involved in the pathogenesis and development of diabetic nephropathy. In addition, signaling pathways mediated by stimulator of interferon gene (STING) and the novel ferroptosis promoter acyl-CoA synthetase long-chain family (ACSL) 1 can induce ferroptosis to promote the progression of diabetic nephropathy. In this review, we focus on the roles of ferroptosis in diabetic nephropathy through the signaling pathways mediated by AMPK, Nrf2/HO-1, TGF-β and exosomes, to elaborate the pathogenesis and development of diabetic nephropathy, and the potential therapeutic target for diabetic nephropathy.
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Affiliation(s)
- Pan Liu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Zhengdong Zhang
- Department of Orthopedics, School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
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Carlos A, Mendes M, Cruz MT, Pais A, Vitorino C. Ferroptosis driven by nanoparticles for tackling glioblastoma. Cancer Lett 2024; 611:217392. [PMID: 39681210 DOI: 10.1016/j.canlet.2024.217392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 12/18/2024]
Abstract
Glioblastoma (GBM) is the most aggressive, malignant, and drug-resistant brain tumor. There are no effective treatment options for GBM, which usually leads to relapses that cause patients to die a few months later. Ferroptosis, a newly discovered mechanism of regulated cell death, has been identified as a tumor suppressor in solid tumors and represents an alternative to apoptosis resistance. This mechanism of cell death is characterized by iron overload, which is responsible for generating reactive oxygen species (ROS) in the cell. Understanding the ferroptosis pathway and its key regulators can be used to develop rational delivery systems that specifically target these regulators in GBM cells and promote cell death. This review conducted a systematic literature search to better understand the potential of ferroptosis as a target for developing nanoparticles to tackle GBM. The mechanisms of action, design parameters, efficacy, and safety concerns of 16 nanoparticles were evaluated, demonstrating the potential of combining ferroptosis inducers with nanocarriers to promote a selective delivery to the tumor microenvironment.
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Affiliation(s)
- Ana Carlos
- Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal
| | - Maria Mendes
- Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Departmente of Chemistry, University of Coimbra, 3004-535, Coimbra, Portugal
| | - Maria T Cruz
- Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Center for Neurosciences and Cell Biology (CNC) and Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548, Coimbra, Portugal
| | - Alberto Pais
- Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Departmente of Chemistry, University of Coimbra, 3004-535, Coimbra, Portugal
| | - Carla Vitorino
- Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal; Coimbra Chemistry Centre, Institute of Molecular Sciences-IMS, Departmente of Chemistry, University of Coimbra, 3004-535, Coimbra, Portugal.
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Wang Z, Zhao M, Huang X, Wang Y, Li W, Qiao J, Yang X. Therapeutic types and advantages of functionalized nanoparticles in inducing ferroptosis in cancer therapy. Ann Med 2024; 56:2396568. [PMID: 39276361 PMCID: PMC11404394 DOI: 10.1080/07853890.2024.2396568] [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: 04/12/2024] [Revised: 06/24/2024] [Accepted: 07/10/2024] [Indexed: 09/17/2024] Open
Abstract
BACKGROUND The clinical efficacy of cancer treatment protocols remains unsatisfactory; however, the emergence of ferroptosis-driven therapy strategies has renewed hope for tumor treatment, owing to their remarkable tumor suppression effects. Biologically based small-molecule inducers are used in conventional method to induce ferroptosis. Nevertheless, some molecular drugs have limited solubility, poor ability to target cells, and fast metabolism, which hinder their ability to induce ferroptosis over a prolonged period. Fortunately, further investigations of ferroptosis and the development of nanotechnology have demonstrated that nanoparticles (NPs) are more efficient in inducing ferroptosis than drugs alone, which opens up new perspectives for cancer therapy. OBJECTIVE In order to organize a profile of recent advance in NPs for inducing ferroptosis in cancer therapy, and NPs were comprehensively classified in a new light.Materials and methods: We comprehensively searched the databases such as PubMed and Embase. The time limit for searching was from the establishment of the database to 2023.11. All literatures were related to "ferroptosis", "nanoparticles", "nanodelivery systems", "tumors", "cancer". RESULTS We summarized and classified the available NPs from a new perspective. The NPs were classified into six categories based on their properties: (1) iron oxide NPs (2) iron - based conversion NPs (3) core-shell structure (4) organic framework (5) silica NPs (6) lipoprotein NPs. According to the therapeutic types of NPs, they can be divided into categories: (1) NPs induced ferroptosis-related immunotherapy (2) NPs loaded with drugs (3) targeted therapy of NPs (4) multidrug resistance therapy (5) gene therapy with NPs (6) energy conversion therapy. CONCLUSIONS The insights gained from this review can provide ideas for the development of original NPs and nanodelivery systems, pave the way for related nanomaterials application in clinical cancer therapy, and advance the application and development of nanotechnology in the medical field.
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Affiliation(s)
- Ziying Wang
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
| | - Miaomiao Zhao
- Department of Pathology, Shandong Second Medical University, Weifang, Shandong, China
| | - Xiaotong Huang
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
| | - Yuxin Wang
- School of Pharmacy, Binzhou Medical College, Yantai, Shandong, China
| | - Wentong Li
- Department of Pathology, Shandong Second Medical University, Weifang, Shandong, China
| | - Jianhong Qiao
- Department of Outpatient, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Xiao Yang
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
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Luo S, Xu J, Mo C, Gong W, Li C, Hou X, Ou M. High-throughput sequencing reveals twelve cell death pattern prognostic target genes as potential drug-response-associated genes in the treatment of colorectal cancer cells with palmatine hydrochloride. ONCOLOGIE 2024. [DOI: 10.1515/oncologie-2024-0378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Objectives
Palmatine Hydrochloride (PaH), an isoquinoline alkaloid from Phellodendron amurense and Coptis chinensis, has analgesic, anti-inflammatory, and anticancer properties. This study aimed to assess PaH’s effectiveness against SW480 colorectal cancer (CRC) cells and explore its molecular mechanisms.
Methods
PaH’s effects on SW480 CRC cells were evaluated using MTT assays for proliferation, scratch assays for migration, and flow cytometry for apoptosis. Differentially expressed genes (DEGs) were identified through high-throughput sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses assessed DEG roles. Prognostic significance related to programmed cell death (PCD) was analyzed using R-Package with TCGA data. RT-qPCR validated key genes identified.
Results
PaH significantly inhibited SW480 cell growth, invasion, and apoptosis. The MTT assay showed inhibition rates increased from 5.49 % at 25 μg/mL to 52.48 % at 400 μg/mL. Scratch assays indicated reduced cell invasion over 24, 48, and 72 h. Apoptosis rose from 12.36 % in controls to 45.54 % at 400 μg/mL. Sequencing identified 3,385 significant DEGs, primarily in cancer pathways (p=0.004). Among 35 PCD-related DEGs, Lasso Cox regression highlighted 12 key genes, including TERT, TGFBR1, WNT4, and TP53. RT-qPCR confirmed TERT and TGFBR1 downregulation (0.614-fold, p=0.008; 0.41-fold, p<0.001) and TP53 and WNT4 upregulation (5.634-fold, p<0.001; 5.124-fold, p=0.002).
Conclusions
PaH inhibits CRC cell proliferation, migration, and invasion by modulating key PCD genes, suggesting its potential as a CRC therapeutic agent.
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Affiliation(s)
- Sha Luo
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
| | - Jiajun Xu
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
| | - Chune Mo
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
| | - Weiwei Gong
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
| | - Chunhong Li
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
| | - Xianliang Hou
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
| | - Minglin Ou
- Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
- Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases , The Second Affiliated Hospital of Guilin Medical University , Guilin, 541199 , China
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Hu H, Zhang G, Tian M, Yin Y, Bao Y, Guan X, Ding C, Yu S. Brucella rough RB51 infection activates P53-Slc7a11-Gpx4/GSH pathway to induce ferroptosis to attenuate the intracellular survival on macrophages. Vet Microbiol 2024; 298:110224. [PMID: 39153287 DOI: 10.1016/j.vetmic.2024.110224] [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: 05/07/2024] [Revised: 07/31/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
B. abortus is a facultative intracellular bacterium that replicates within macrophages. Intracellular survival is one of the important indexes to evaluate the virulence of Brucella. Ferroptosis is a type of programmed cell death induced by the accumulation of free iron, reactive oxygen species (ROS), and toxic lipid peroxides, play roles on cancers, cardiovascular diseases, and inflammatory diseases. In this study, we found that Brucella rough strain RB51 induced ferroptosis on macrophages with reduced levels of host glutathione and glutathione peroxidase 4 (Gpx4), together with increased ferrous iron, lipid peroxidation, and ROS. The inhibitor ferrostatin-1 significantly reduced the ferroptosis of RB51-infected macrophages, confirming that ferroptosis occurred during infection with Brucella RB51. Furthermore, we found that RB51 infection induced ferroptosis is regulated by P53-Slc7a11-Gpx4/GSH signal pathway. Inhibiting P53 decreased the levels of ROS and lipid peroxidation, while the levels of Slc7a11, Gpx4 and GSH were rescued. More importantly, inhibiting ferroptosis by different ferroptosis inhibitors increased the intracellular survival of Brucella RB51, indicating ferroptosis functions on the attenuation of Brucella intracellular survival. Collectively, our observations demonstrate that Brucella RB51 infection induces ferroptosis on macrophages, which is regulated by P53-Slc7a11-Gpx4/GSH signal pathway and functions on the attenuation of intracellular survival of Brucella.
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Affiliation(s)
- Hai Hu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China
| | - Guangdong Zhang
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China
| | - Mingxing Tian
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China
| | - Yi Yin
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China
| | - Yanqing Bao
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China
| | - Xiang Guan
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China
| | - Chan Ding
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China; School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, PR China.
| | - Shengqing Yu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, PR China; Jiangsu Key Laboratory for High-Tech Research and Development of Veterinary Biopharmaceuticals, Jiangsu Agri-Animal Husbandry Vocational College, Veterinary Bio-Pharmaceutical, Taizhou, China.
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Pei Z, Fan J, Tang M, Li Y. Ferroptosis: A New Strategy for the Treatment of Fibrotic Diseases. Adv Biol (Weinh) 2024:e2400383. [PMID: 39377183 DOI: 10.1002/adbi.202400383] [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: 07/02/2024] [Revised: 09/07/2024] [Indexed: 10/09/2024]
Abstract
Ferroptosis is a new type of cell death characterized by iron dependence and the excessive accumulation of lipid reactive oxygen species (lipid ROS) that has gradually become better characterized. There is sufficient evidence indicating that ferroptosis is associated with a variety of human life activities and diseases, such as tumor suppression, ischemic organ injury, and degenerative disorders. Notably, ferroptosis is also involved in the initiation and development of fibrosis in various organs, including liver fibrosis, pulmonary fibrosis, renal fibrosis, and cardiac fibrosis, which is usually irreversible and refractory. Although a large number of patients with fibrosis urgently need to be treated, the current treatment options are still limited and unsatisfactory. Organ fibrosis involves a series of complex and orderly processes, such as parenchymal cell damage, recruitment of inflammatory cells and activation of fibroblasts, which ultimately leads to the accumulation of extracellular matrix (ECM) and the formation of fibrosis. An increasing number of studies have confirmed the close association between these pathological processes and ferroptosis. This review summarizes the role and function of ferroptosis in fibrosis and proposes several potential therapeutic strategies and pathways based on ferroptosis.
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Affiliation(s)
- Zhuo Pei
- Air Force Hospital of the Central Theater Command of PLA, Datong, 037006, China
| | - Jing Fan
- Air Force Hospital of the Northern Theater Command of the People's Liberation Army of China, Shenyang, 110044, China
| | - Maolin Tang
- Air Force Hospital of the Central Theater Command of PLA, Datong, 037006, China
| | - Yuhong Li
- Department of Cell Biology, Army Medical University, Chongqing, 400038, China
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Sun S, Li H, Liu S, Xie X, Zhai W, Pan J. Long noncoding RNA UCA1 inhibits epirubicin-induced apoptosis by activating PPARα-mediated lipid metabolism. Exp Cell Res 2024; 442:114271. [PMID: 39357639 DOI: 10.1016/j.yexcr.2024.114271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 10/04/2024]
Abstract
Metabolic reprogramming is a hallmark of cancer, and abnormal lipid metabolism is associated with drug resistance in bladder cancer cells. The long noncoding RNA (lncRNA) UCA1 is overexpressed in bladder cancer, but its functional contribution to lipid metabolism remains uncharacterized. In this study, we demonstrated that lncRNA UCA1 inhibits epirubicin-induced cell apoptosis by supporting abnormal lipid metabolism in bladder cancer cells. Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARα mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARα and downstream p-AKT/p-GSK-3β/β-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRα to the lncRNA UCA1 promoter. These findings were verified in a mouse xenograft model and are consistent with the expression patterns in human bladder cancer patients. Overall, these findings establish the role of lncRNA UCA1 in lipid metabolism and bladder cancer cell resistance to epirubicin, suggesting that lncRNA UCA1 may serve as a candidate target for enhancing bladder cancer chemotherapy.
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Affiliation(s)
- Shuaijie Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Zhengzhou, China
| | - Huijin Li
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Shanshan Liu
- Department of Clinical Laboratory, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xiaojuan Xie
- Shaanxi Center for Clinical Laboratory, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Wen Zhai
- Department of Medical Genetics, Northwest Women's and Children's Hospital, Xi'an, China
| | - Jingjing Pan
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and the Key Clinical Laboratory of Henan Province, Zhengzhou, 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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Ashoub MH, Amiri M, Fatemi A, Farsinejad A. Evaluation of ferroptosis-based anti-leukemic activities of ZnO nanoparticles synthesized by a green route against Pre-B acute lymphoblastic leukemia cells (Nalm-6 and REH). Heliyon 2024; 10:e36608. [PMID: 39263164 PMCID: PMC11387337 DOI: 10.1016/j.heliyon.2024.e36608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/13/2024] Open
Abstract
Background Our research presents an efficient and practical method for producing Zinc Oxide nanoparticles (ZnO NPs), which have anti-leukemic effects based on ferroptosis. Methods The black cardamom extract was employed as a capping and reducing agent for the green synthesis. The NPs have been characterized via scanning electron microscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. Additionally, leukemic and normal cells were exposed to ZnO NPs (25, 50, 75, 100, 150, 200, and 300 μg/mL) for 24 and 48 h. The cell vitality was then measured using the MTT test. Moreover, ferroptosis indicators were assessed via commercial testing kits, and finally, qRT-PCR and flow cytometry were used to measure gene expression and cell death. Results The findings displayed that green synthesized ZnO NPs reduced the survival of leukemic cells, with IC50 values of 150.89 μg/ml for Nalm-6 and 101.31 μg/ml for REH cells after 48 h. The ZnO NPs increased ferroptosis by significantly increasing MDA, intracellular iron, ACSL4, ALOX15, and p53 mRNA expressions while significantly decreasing GSH and GPx activity levels and SLC7A11 and GPx4 mRNA expressions. On the other hand, ZnO NPs exhibited no toxicity toward normal cells. Conclusions The research suggests that ZnO NPs synthesized using the green approach can induce ferroptosis in leukemic cells by disrupting redox homeostasis and increasing intracellular iron levels, potentially enhancing the benefits of anti-leukemic therapies in the future.
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Affiliation(s)
- Muhammad Hossein Ashoub
- Stem Cells and Regenerative Medicine Innovation Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mahnaz Amiri
- Stem Cells and Regenerative Medicine Innovation Center, Kerman University of Medical Sciences, Kerman, Iran
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Science, Kerman, Iran
| | - Ahmad Fatemi
- Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | - Alireza Farsinejad
- Student Research Committee, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
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12
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Xia J, Fu B, Wang Z, Wen G, Gu Q, Chen D, Ren H. MVP enhances FGF21-induced ferroptosis in hepatocellular carcinoma by increasing lipid peroxidation through regulation of NOX4. Clin Transl Sci 2024; 17:e13910. [PMID: 39143889 PMCID: PMC11325046 DOI: 10.1111/cts.13910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/08/2024] [Accepted: 07/19/2024] [Indexed: 08/16/2024] Open
Abstract
Ferroptosis is a novel, iron-dependent regulatory cell death mainly caused by an imbalance between the production and degradation of intracellular reactive oxygen species (ROS). Recently, ferroptosis induction has been considered a potential therapeutic approach for hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) is a new modulator of ferroptosis; however, the regulatory role of FGF21 in HCC ferroptosis has not been investigated. In this study, we explored the role of FGF21 and its underlying molecular mechanism in the ferroptotic death of HCC cells. We identified Major vault protein (MVP) as a target of FGF21 and revealed that knockdown of MVP inhibited the lipid peroxidation levels of HCC cells by decreasing NADPH oxidase 4 (NOX4, a major source of ROS) transcription, thereby attenuating the effect of FGF21-mediated ferroptosis. On the other hand, MVP overexpression showed the opposite results. Mechanistically, MVP binds to IRF1 and thus interferes with the interaction between IRF1 and the YAP1 promoter, leading to an increase in NOX4 transcription. Importantly, forced expression of IRF1 or downregulation of YAP1 partially reversed the effect of MVP overexpression on HCC ferroptosis. Furthermore, the results in xenograft tumor models suggested that overexpression of MVP can efficiently increase the level of lipid peroxidation in vivo. Taken together, these results provide new insights into the regulatory mechanism of ferroptosis in HCC.
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Affiliation(s)
- Jinkun Xia
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Hepatobiliary Institute, Nanjing Drum Tower Hospital, Medical SchoolNanjing UniversityNanjingChina
| | - Boqi Fu
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Zhe Wang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Gaolin Wen
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Quanshui Gu
- Department of Anesthesia SurgeryNanjing University Medical School Affiliated Nanjing Drum Tower HospitalNanjingChina
| | - Dayu Chen
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Hepatobiliary Institute, Nanjing Drum Tower Hospital, Medical SchoolNanjing UniversityNanjingChina
- Department of PharmacyNanjing University Medical School Affiliated Nanjing Drum Tower HospitalNanjingChina
| | - Haozhen Ren
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Hepatobiliary Institute, Nanjing Drum Tower Hospital, Medical SchoolNanjing UniversityNanjingChina
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13
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Zhou K, Wang D, Du X, Feng X, Zhu X, Wang C. UBE2C enhances temozolomide resistance by regulating the expression of p53 to induce aerobic glycolysis in glioma. Acta Biochim Biophys Sin (Shanghai) 2024; 56:916-926. [PMID: 38634120 PMCID: PMC11214954 DOI: 10.3724/abbs.2024033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 01/23/2024] [Indexed: 04/19/2024] Open
Abstract
UBE2C is overexpressed in gliomas, and its overexpression has been reported to be correlated with the drug resistance of gliomas to some extent. In this study, we explore the role of UBE2C in regulating temozolomide (TMZ) resistance in glioma and investigate the underlying mechanisms involved. Twenty normal brain tissues and 100 glioma tissues from 50 TMZ-resistant patients and 50 TMZ-sensitive patients are included in this study. TMZ-resistant cell lines are constructed to explore the role of UBE2C in regulating glioma cell viability and TMZ resistance. Our results show that both the mRNA and protein levels of UBE2C are significantly elevated in the brain tissues of glioma patients, especially in those of TMZ-resistant patients. Consistently, UBE2C expression is markedly upregulated in TMZ-resistant cell lines. Overexpression of UBE2C rescues glioma cells from TMZ-mediated apoptosis and enhances cell viability. In contrast, downregulation of UBE2C expression further enhances TMZ function, increases cell apoptosis and decreases cell viability. Mechanistically, UBE2C overexpression decreases p53 expression and enhances aerobic glycolysis level by increasing ATP level, lactate production, and glucose uptake. Downregulation of p53 level abolishes the role of UBE2C downregulation in inhibiting TMZ resistance and aerobic glycolysis in glioma cells. Moreover, an animal assay confirms that downregulation of UBE2C expression further suppresses tumor growth in the context of TMZ treatment. Collectively, this study reveals that downregulation of UBE2C expression enhances the sensitivity of glioma cells to TMZ by regulating the expression of p53 to inhibit aerobic glycolysis.
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Affiliation(s)
- Kun Zhou
- Department of Neurosurgerythe Jinyang Hospital Affiliated to Guizhou Medical UniversityGuiyang550084China
| | - Dexin Wang
- Department of Neurosurgerythe Jinyang Hospital Affiliated to Guizhou Medical UniversityGuiyang550084China
| | - Xiaolin Du
- Department of Neurosurgerythe Jinyang Hospital Affiliated to Guizhou Medical UniversityGuiyang550084China
| | - Xia Feng
- Department of Sleep Medicinethe Second People’s Hospital of Guizhou ProvinceGuiyang550084China
| | - Xiaoxi Zhu
- Key Laboratory of Cell Engineering of Guizhou ProvinceAffiliated Hospital of Zunyi Medical UniversityZunyi563000China
| | - Cheng Wang
- Department of Neurosurgerythe Jinyang Hospital Affiliated to Guizhou Medical UniversityGuiyang550084China
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14
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Liao Y, Wei F, He Z, He J, Ai Y, Guo C, Zhou L, Luo D, Li C, Wen Y, Zeng J, Ma X. Animal-derived natural products for hepatocellular carcinoma therapy: current evidence and future perspectives. Front Pharmacol 2024; 15:1399882. [PMID: 38803433 PMCID: PMC11129636 DOI: 10.3389/fphar.2024.1399882] [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: 03/12/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate, and the survival rate of HCC patients remains low. Animal medicines have been used as potential therapeutic tools throughout the long history due to their different structures of biologically active substances with high affinity to the human body. Here, we focus on the effects and the mechanism of action of animal-derived natural products against HCC, which were searched in databases encompassing Web of Science, PubMed, Embase, Science Direct, Springer Link, and EBSCO. A total of 24 natural products from 12 animals were summarized. Our study found that these natural products have potent anti-hepatocellular carcinoma effects. The mechanism of action involving apoptosis induction, autophagy induction, anti-proliferation, anti-migration, and anti-drug resistance via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), Ras/extracellular signal regulated kinases (ERK)/mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Huachansu injection and sodium cantharidate have been used in clinical applications with good efficacy. We review the potential of animal-derived natural products and their derivatives in the treatment of HCC to date and summarize their application prospect and toxic side effects, hoping to provide a reference for drug development for HCC.
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Affiliation(s)
- Yichao Liao
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Feng Wei
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhelin He
- Endoscopy Center, Guang’an Hospital of Traditional Chinese Medicine, Guang’an, China
| | - Jingxue He
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanlin Ai
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cui Guo
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Zhou
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dan Luo
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chengen Li
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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15
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Ascenzi F, Esposito A, Bruschini S, Salvati V, De Vitis C, De Arcangelis V, Ricci G, Catizione A, di Martino S, Buglioni S, Bassi M, Venuta F, De Nicola F, Massacci A, Grassucci I, Pallocca M, Ricci A, Fanciulli M, Ciliberto G, Mancini R. Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells. Cell Death Dis 2024; 15:303. [PMID: 38684666 PMCID: PMC11059184 DOI: 10.1038/s41419-024-06667-w] [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: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 05/02/2024]
Abstract
Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.
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Affiliation(s)
- Francesca Ascenzi
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
- Department of Clinical and Molecular Medicine, Sant' Andrea Hospital-Sapienza University of Rome, Rome, Italy
| | - Antonella Esposito
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Sara Bruschini
- Department of Clinical and Molecular Medicine, Sant' Andrea Hospital-Sapienza University of Rome, Rome, Italy
- SAFU Laboratory, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Valentina Salvati
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Claudia De Vitis
- Department of Clinical and Molecular Medicine, Sant' Andrea Hospital-Sapienza University of Rome, Rome, Italy
| | - Valeria De Arcangelis
- Department of Clinical and Molecular Medicine, Sant' Andrea Hospital-Sapienza University of Rome, Rome, Italy
| | - Giulia Ricci
- Department of Experimental Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy
| | - Angiolina Catizione
- Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy
| | - Simona di Martino
- Pathology Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Simonetta Buglioni
- Pathology Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | | | - Federico Venuta
- Thoracic Surgery Unit, Sapienza University of Rome, Rome, Italy
| | | | - Alice Massacci
- Biostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Isabella Grassucci
- Biostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Matteo Pallocca
- Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Alberto Ricci
- Respiratory Unit, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Maurizio Fanciulli
- SAFU Laboratory, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Gennaro Ciliberto
- Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Rita Mancini
- Department of Clinical and Molecular Medicine, Sant' Andrea Hospital-Sapienza University of Rome, Rome, Italy.
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16
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Zhang T, Luo L, He Q, Xiao S, Li Y, Chen J, Qin T, Xiao Z, Ge Q. Research advances on molecular mechanism and natural product therapy of iron metabolism in heart failure. Eur J Med Res 2024; 29:253. [PMID: 38659000 PMCID: PMC11044586 DOI: 10.1186/s40001-024-01809-4] [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: 08/09/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.
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Affiliation(s)
- Tianqing Zhang
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Li Luo
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Qi He
- People's Hospital of Ningxiang City, Ningxiang City, China
| | - Sijie Xiao
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Yuwei Li
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Junpeng Chen
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Tao Qin
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Zhenni Xiao
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China
| | - Qingliang Ge
- Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University, Hunan, China.
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Guo M, Du X, Wang X. Inhibition of ferroptosis: A new direction in the treatment of ulcerative colitis by traditional Chinese medicine. JOURNAL OF ETHNOPHARMACOLOGY 2024; 324:117787. [PMID: 38253272 DOI: 10.1016/j.jep.2024.117787] [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: 09/20/2023] [Revised: 12/22/2023] [Accepted: 01/15/2024] [Indexed: 01/24/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is a chronic idiopathic intestinal disease of unknown cause and has been classified as one of the modern intractable diseases by the World Health Organization (WHO). Ferroptosis, as an iron-ion-dependent mode of programmed cell death, is closely related to iron metabolism, lipid peroxidation, and imbalance of the antioxidant system, and plays an important role in the development of UC. In this paper, we will review the regulatory pathways of ferroptosis, the relationship between ferroptosis and the pathogenesis of UC, and the treatment of UC by TCM from the perspective of ferroptosis inhibition, and summarize the mechanism of action of the active ingredients of TCM and TCM compounds to improve UC through ferroptosis inhibition, and look forward to the prospect of the application of ferroptosis inhibition by TCM in the treatment of UC. AIM OF THIS REVIEW This paper aims to elucidate the mechanism of action of TCM active ingredients and TCM combinations in the treatment of UC by inhibiting ferroptosis. The active ingredients of TCM have the significant advantages of multi-targets and multi-pathways, and ferroptosis is the current research hotspot in the prevention and treatment of UC, so the inhibition of ferroptosis by TCM is a key direction for future research. MATERIALS AND METHODS The keywords "ferroptosis", "ulcerative colitis" and "TCM" were searched in Pubmed, CNKI, and Wed of Science databases. Papers related to clinical trials and pharmacological research up to August 2023 were screened for inclusion. Combined with the theory of TCM, we systematically summarized the effects of TCM active ingredients and TCM combinations in inhibiting ferroptosis and thus preventing UC. RESULTS A large number of studies have shown that TCM active ingredients and TCM combinations inhibit the inflammatory response and oxidative stress in the course of UC mainly by interfering with iron metabolism, correcting lipid metabolism and peroxidative accumulation, and regulating the processes of glutathione (GSH) and glutathione peroxidase 4 (GPX4), to improve colonic mucosal damage and promote the repair of colonic mucosal tissue. CONCLUSION Since the study of ferroptosis in UC is still in the exploratory stage, many issues still deserve attention in the future. This paper reviews the mechanism of ferroptosis inhibition by TCM active ingredients and TCM combinations to prevent and treat UC. In the future, we should also further increase the number of clinical experimental studies to explore whether more TCM medicines can play a therapeutic role in UC by inhibiting ferroptosis, and explore more pathways and genes targeting the inhibition of ferroptosis, to seek more TCM therapies for UC. We believe that the use of TCM active ingredients and TCM combinations to regulate ferroptosis is an important direction for future UC prevention and treatment.
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Affiliation(s)
- Meitong Guo
- College of Traditional Chinese Medicine, Changchun University of Traditional Chinese Medicine, No.1035, Boshuo Road, Jingyue National Hi-Tech Industrial Development Zone, Changchun, 130117, China.
| | - Xingchen Du
- College of Basic Medical Sciences, Changchun University of Traditional Chinese Medicine, No.1035, Boshuo Road, Jingyue National Hi-Tech Industrial Development Zone, Changchun, 130117, China.
| | - Xiaoyan Wang
- The First Clinical Hospital of Jilin Academy of Traditional Chinese Medical Sciences, Changchun Economic and Technological Development Zone, No. 6426, Changchun, China.
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18
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Yu S, Tong L, Shen J, Li C, Hu Y, Feng K, Shao J. Recent research progress based on ferroptosis-related signaling pathways and the tumor microenvironment on it effects. Eur J Med Chem 2024; 269:116290. [PMID: 38518522 DOI: 10.1016/j.ejmech.2024.116290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/19/2024] [Accepted: 02/25/2024] [Indexed: 03/24/2024]
Abstract
The existing therapies for cancer are not remote satisfactory due to drug-resistance in tumors that are malignant. There is a pressing necessity to take a step forward to develop innovative therapies that can complement current ones. Multiple investigations have demonstrated that ferroptosis therapy, a non-apoptotic modality of programmed cell death, has tremendous potential in face of multiple crucial events, such as drug resistance and toxicity in aggressive malignancies. Recently, ferroptosis at the crosswalk of chemotherapy, materials science, immunotherapy, tumor microenvironment, and bionanotechnology has been presented to elucidate its therapeutic feasibility. Given the burgeoning progression of ferroptosis-based nanomedicine, the newest advancements in this field at the confluence of ferroptosis-inducers, nanotherapeutics, along with tumor microenvironment are given an overview. Here, the signaling pathways of ferroptosis-related were first talked about briefly. The emphasis discussion was placed on the pharmacological mechanisms and the nanodrugs design of ferroptosis inducing agents based on multiple distinct metabolism pathways. Additionally, a comprehensive overview of the action mechanisms by which the tumor microenvironment influences ferroptosis was elaborately descripted. Finally, some limitations of current researches and future research directions were also deliberately discussed to provide details about therapeutic avenues for ferroptosis-related diseases along with the design of anti-drugs.
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Affiliation(s)
- Shijing Yu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Lingwu Tong
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Jiangwen Shen
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Chenglei Li
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Yongshan Hu
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Keke Feng
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China
| | - Jingwei Shao
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, China.
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19
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Liu P, Zhang Z, Cai Y, Li Z, Zhou Q, Chen Q. Ferroptosis: Mechanisms and role in diabetes mellitus and its complications. Ageing Res Rev 2024; 94:102201. [PMID: 38242213 DOI: 10.1016/j.arr.2024.102201] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 01/06/2024] [Accepted: 01/15/2024] [Indexed: 01/21/2024]
Abstract
Diabetes mellitus (DM) and its complications are major diseases that affect human health and pose a serious threat to global public health. Although the prevention and treatment of DM and its complications are constantly being revised, optimal treatment strategies remain unavailable. Further exploration of new anti-diabetic strategies is an arduous task. Revealing the pathological changes and molecular mechanisms of DM and its complications is the cornerstone for exploring new therapeutic strategies. Ferroptosis is a type of newly discovered iron-dependent regulated cell death. Notably, the role of ferroptosis in the occurrence, development, and pathogenesis of DM and its complications has gradually been revealed. Numerous studies have shown that ferroptosis plays an important role in the pathophysiology and pathogenesis of DM and its associated complications. The aim of this review is to discuss the known underlying mechanisms of ferroptosis, the relationship between ferroptosis and DM, and the relationship between ferroptosis as a mode of cell death and diabetic kidney disease, diabetic retinopathy, diabetic cardiomyopathy, diabetic osteoporosis, diabetes-associated cognitive dysfunction, DM-induced erectile dysfunction, and diabetic atherosclerosis.
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Affiliation(s)
- Pan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, PR China
| | - Zhengdong Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, Sichuan, PR China; Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan, PR China
| | - Yichen Cai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, PR China
| | - Zhaoying Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, PR China
| | - Qian Zhou
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, PR China
| | - Qiu Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan, PR China.
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20
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Tian W, Wan X, Tian L, Wu Y, Cui X, Yi J. New molecular insights into ferroptosis in lung adenocarcinoma progression and pharmacological compounds for targeted therapy. J Gene Med 2024; 26:e3579. [PMID: 37581210 DOI: 10.1002/jgm.3579] [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: 05/16/2023] [Revised: 07/13/2023] [Accepted: 07/24/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND The involvement of ferroptosis has been found in many pathological conditions of the lung. The genetic engineering of ferroptosis-related genes may provide a potential target for the treatment of lung adenocarcinoma (LUAD). METHODS Nine ferroptosis regulators and markers were collected from FerrDb and their somatic mutations and expressions were analyzed based on The Cancer Genome Atlas (TCGA)-LUAD cohort data. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to screen genes significantly associated with ferroptosis. The ferroptosis-related gene signature was constructed using TCGA-LUAD cohort data and was verified using the GSE cohort with pooled data for GSE30219, GSE31210, GSE37745 and GSE50081. Immune microenvironment component and mutation analysis were performed for genes in the ferroptosis-related gene signature. RESULTS All nine ferroptosis regulators and markers were differentially expressed between normal LUAD tumor tissues and adjacent normal tissues and were related to copy number variation. The expression of 1329 genes were significantly associated with nine ferroptosis regulators and markers in the TCGA-LUAD dataset, five (ALDOA, PLK1, CD47, CENPC and TMOD3) of which were integrated into a ferroptosis-related gene signature to calculate the risk score of LUAD samples, showing a significant correlation with the abundance of immune cell infiltration and the immune score. Molecular docking showed the binding activity of natural active compound quercetin to target proteins ALDOA and CD47, as well as the binding activity of aristolochic acid to PLK1 protein and TMOD3 protein. CONCLUSIONS In the present study, a ferroptosis-related gene signature with predictive value for LUAD prognosis was constructed, in which the gene was a potential therapeutic target for LUAD. Quercetin and aristolochic acid were potential candidates for inhibiting these targets by directly binding to them and showing high affinity and strong stability.
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Affiliation(s)
- Wenhui Tian
- Pharmacy Department, Zhejiang Hospital, Hangzhou, China
| | - Xiaoqing Wan
- Pharmacy Department, Zhejiang Hospital, Hangzhou, China
| | - Lili Tian
- Pharmacy Department, Zhejiang Hospital, Hangzhou, China
| | - Yajun Wu
- Pharmacy Department, Zhejiang Hospital, Hangzhou, China
| | - Xiaohua Cui
- Pharmacy Department, Zhejiang Hospital, Hangzhou, China
| | - Jingyu Yi
- Pharmacy Department, Zhejiang Hospital, Hangzhou, China
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21
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Endale HT, Tesfaye W, Mengstie TA. ROS induced lipid peroxidation and their role in ferroptosis. Front Cell Dev Biol 2023; 11:1226044. [PMID: 37601095 PMCID: PMC10434548 DOI: 10.3389/fcell.2023.1226044] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Reactive oxygen species (ROS) play a crucial part in the process of cell death, including apoptosis, autophagy, and ferroptosis. ROS involves in the oxidation of lipids and generate 4-hydroxynonenal and other compounds associated with it. Ferroptosis may be facilitated by lipid peroxidation of phospholipid bilayers. In order to offer novel ideas and directions for the investigation of disorders connected to these processes, we evaluate the function of ROS in lipid peroxidation which ultimately leads to ferroptosis as well as proposed crosstalk mechanisms between ferroptosis and other types programmed cell death.
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Affiliation(s)
- Hiwot Tezera Endale
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Winta Tesfaye
- Department of Human Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Tiget Ayelgn Mengstie
- Department of Human Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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22
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Zeng XY, Qiu XZ, Wu JN, Liang SM, Huang JA, Liu SQ. Interaction mechanisms between autophagy and ferroptosis: Potential role in colorectal cancer. World J Gastrointest Oncol 2023; 15:1135-1148. [PMID: 37546557 PMCID: PMC10401467 DOI: 10.4251/wjgo.v15.i7.1135] [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: 02/03/2023] [Revised: 03/28/2023] [Accepted: 04/23/2023] [Indexed: 07/12/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignancy that has the second highest incidence and mortality rate. Although there are many personalized treatment options for CRC, the therapeutic effects are ultimately limited by drug resistance. Studies have aimed to block the initiation and progression of CRC by inducing cell death to overcome this obstacle. Substantial evidence has indicated that both autophagy and ferroptosis play important regulatory roles in CRC. Autophagy, a lysosome-dependent process by which cellular proteins and organelles are degraded, is the basic mechanism for maintaining cell homeostasis. The duality and complexity of autophagy in cancer therapy is a hot topic of discussion. Ferroptosis, a regulated cell death pathway, is associated with iron accumulation-induced lipid peroxidation. The activation of ferroptosis can suppress CRC proliferation, invasion and drug resistance. Furthermore, recent studies have suggested an interaction between autophagy and ferroptosis. Autophagy can selectively degrade certain cellular contents to provide raw materials for ferroptosis, ultimately achieving antitumor and anti-drug resistance. Therefore, exploring the interaction between autophagy and ferroptosis could reveal novel ideas for the treatment of CRC. In this review, we describe the mechanisms of autophagy and ferroptosis, focusing on their roles in CRC and the crosstalk between them.
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Affiliation(s)
- Xin-Ya Zeng
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Xin-Ze Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jiang-Ni Wu
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Mei Liang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jie-An Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Shi-Quan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
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23
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Koeberle SC, Kipp AP, Stuppner H, Koeberle A. Ferroptosis-modulating small molecules for targeting drug-resistant cancer: Challenges and opportunities in manipulating redox signaling. Med Res Rev 2023; 43:614-682. [PMID: 36658724 PMCID: PMC10947485 DOI: 10.1002/med.21933] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/07/2022] [Accepted: 01/03/2023] [Indexed: 01/21/2023]
Abstract
Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system Xc - that is central for glutathione regeneration, (iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase-1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.
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Affiliation(s)
- Solveigh C. Koeberle
- Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
- Department of Molecular Nutritional Physiology, Institute of Nutritional SciencesFriedrich Schiller University JenaThüringenJenaGermany
| | - Anna P. Kipp
- Department of Molecular Nutritional Physiology, Institute of Nutritional SciencesFriedrich Schiller University JenaThüringenJenaGermany
| | - Hermann Stuppner
- Unit of Pharmacognosy, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
| | - Andreas Koeberle
- Michael Popp Institute, Center for Molecular Biosciences Innsbruck (CMBI)University of InnsbruckTirolInnsbruckAustria
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24
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Akiyama H, Carter BZ, Andreeff M, Ishizawa J. Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia. Cells 2023; 12:1128. [PMID: 37190037 PMCID: PMC10136912 DOI: 10.3390/cells12081128] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/04/2023] [Accepted: 04/07/2023] [Indexed: 05/17/2023] Open
Abstract
Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is largely lacking. In this review, we summarize the current understanding of ferroptosis-regulating mechanisms with respect to the metabolism of phospholipids and iron as well as major anti-oxidative pathways that protect cells from ferroptosis. We also highlight the diverse impact of p53, a master regulator of cell death and cellular metabolic processes, on the regulation of ferroptosis. Lastly, we discuss recent ferroptosis studies in leukemia and provide a future perspective for the development of promising anti-leukemia therapies implementing ferroptosis induction.
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Affiliation(s)
| | | | | | - Jo Ishizawa
- Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (H.A.); (B.Z.C.); (M.A.)
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25
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Zheng F, Wang Y, Zhang Q, Chen Q, Liang CL, Liu H, Qiu F, Chen Y, Huang H, Lu W, Dai Z. Polyphyllin I suppresses the gastric cancer growth by promoting cancer cell ferroptosis. Front Pharmacol 2023; 14:1145407. [PMID: 37081971 PMCID: PMC10110865 DOI: 10.3389/fphar.2023.1145407] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023] Open
Abstract
Background: Ferroptosis is a new form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides and membrane damages. Recent studies have identified an important role for cancer cell ferroptosis in antitumor therapy. On the other hand, polyphyllin I (PPI) has been reported to exert antitumor effects on some types of cancers. However, it remains unknown whether or not PPI regulates cancer cell ferroptosis.Methods: Two types of human gastric cancer cells (AGS and MKN-45) were used to establish tumor xenograft models in nude mice that were treated with polyphyllin I (PPI) to observe tumor growth, while cells also were cultured for in vitro studies. Ferroptosis, based on the intracellular ROS/lipid ROS production and accumulation of ferrous ions, was detected using a fluorescence microscope and flow cytometer, while the expression of NRF2/FTH1 was measured using Western blotting assays.Results: Here we found that PPI inhibited the gastric cancer growth in vivo and in vitro while increasing the intracellular reactive oxygen species (ROS)/lipid peroxides and ferrous ions in the gastric cancer cells. PPI also decreased the levels of nuclear factor erythroid 2-related factor 2 (NRF2) and ferritin heavy chain 1 (FTH1) in gastric cancer cells in vitro. Moreover, liproxstain-1, an inhibitor of cell ferroptosis, mostly reversed the cell ferroptosis and tumor growth arrest induced by PPI. Finally, the effects of PPI on cancer cell ferroptosis were diminished by the overexpression of NRF2.Conclusion: For the first time, our results have demonstrated that PPI exerts its antitumor activity on the gastric cancer by, at least partially, inducing cancer cell ferroptosis via regulating NRF2/FTH1 pathway. These findings may be implicated for clinical replacement therapy of the gastric cancer.
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Affiliation(s)
- Fang Zheng
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Yeshu Wang
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Qunfang Zhang
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Qiuyuan Chen
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Chun-Ling Liang
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Huazhen Liu
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Feifei Qiu
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuchao Chen
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Haiding Huang
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
| | - Weihui Lu
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
- *Correspondence: Weihui Lu, ; Zhenhua Dai,
| | - Zhenhua Dai
- Section of Immunology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
- Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China
- *Correspondence: Weihui Lu, ; Zhenhua Dai,
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26
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Liu H, Yan J, Guan F, Jin Z, Xie J, Wang C, Liu M, Liu J. Zeaxanthin prevents ferroptosis by promoting mitochondrial function and inhibiting the p53 pathway in free fatty acid-induced HepG2 cells. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159287. [PMID: 36690321 DOI: 10.1016/j.bbalip.2023.159287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 01/03/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder worldwide and a risk factor for obesity and diabetes. Emerging evidence has shown that ferroptosis is involved in the progression of NAFLD. Zeaxanthin (ZEA) is a carotenoid found in human serum. It has been reported that ZEA can ameliorate obesity, prevent age-related macular degeneration, and protect against non-alcoholic steatohepatitis. However, no study has focused on the protective effects of ZEA against NAFLD. In this study, free fatty acid (FFA) induced HepG2 cells were used as a cell model for NAFLD. Our results suggest that ZEA exerts antioxidative and anti-inflammatory effects in FFA-induced HepG2 cells. Moreover, ZEA acted as a ferroptosis inhibitor, significantly reducing reactive oxygen species (ROS) generation and iron overload and improving mitochondrial dysfunction in FFA-induced HepG2 cells. In addition, ZEA downregulated the expression of p53 and modulated downstream targets, such as GPX4, SLC7A11, SAT1, and ALOX15, which contributed to the reduction in cellular lipid peroxidation. Our findings suggest that ZEA has the potential for NAFLD intervention.
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Affiliation(s)
- Huimin Liu
- College of Life Science, Jilin Agricultural University, Changchun, Jilin 130118, China; College of Food Science and Engineering, Jilin Agricultural University, Changchun, Jilin 130118, China; National Engineering Research Center for Wheat and Corn Deep Processing, Changchun, Jilin 130118, China.
| | - Jie Yan
- College of Life Science, Jilin Agricultural University, Changchun, Jilin 130118, China
| | - Fengtao Guan
- College of Life Science, Jilin Agricultural University, Changchun, Jilin 130118, China
| | - Zhibo Jin
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, Jilin 130118, China; National Engineering Research Center for Wheat and Corn Deep Processing, Changchun, Jilin 130118, China
| | - Jiahan Xie
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, Jilin 130118, China; National Engineering Research Center for Wheat and Corn Deep Processing, Changchun, Jilin 130118, China
| | - Chongrui Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, Jilin 130118, China
| | - Meihong Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, Jilin 130118, China; National Engineering Research Center for Wheat and Corn Deep Processing, Changchun, Jilin 130118, China
| | - Jingsheng Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, Jilin 130118, China; National Engineering Research Center for Wheat and Corn Deep Processing, Changchun, Jilin 130118, China.
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27
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Wang L, Pan S. The regulatory effects of p53 on the typical and atypical ferroptosis in the pathogenesis of osteosarcoma: A systematic review. Front Genet 2023; 14:1154299. [PMID: 37065475 PMCID: PMC10090352 DOI: 10.3389/fgene.2023.1154299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/01/2023] [Indexed: 03/31/2023] Open
Abstract
Study background: As a rare condition, osteosarcoma affects approximately 3% of all cancer patients. Its exact pathogenesis remains largely unclear. The role of p53 in up- and down-regulating atypical and typical ferroptosis in osteosarcoma remains unclear. The primary objective of the present study is investigating the role of p53 in regulating typical and atypical ferroptosis in osteosarcoma. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Patient, Intervention, Comparison, Outcome, and Studies (PICOS) protocol were used in the initial search. The literature search was performed in six electronic databases, including EMBASE, Cochrane library of trials, Web of Science, PubMed, Google Scholar, and Scopus Review, using keywords connected by Boolean operators. We focused on studies that adequately defined patient profiles described by PICOS. Results and discussion: We found that p53 played fundamental up- and down-regulatory roles in typical and atypical ferroptosis, resulting in either advancement or suppression of tumorigenesis, respectively. Direct and indirect activation or inactivation of p53 downregulated its regulatory roles in ferroptosis in osteosarcoma. Enhanced tumorigenesis was attributed to the expression of genes associated with osteosarcoma development. Modulation of target genes and protein interactions, especially SLC7A11, resulted in enhanced tumorigenesis. Conclusion: Typical and atypical ferroptosis in osteosarcoma were regulatory functions of p53. The activation of MDM2 inactivated p53, leading to the downregulation of atypical ferroptosis, whereas activation of p53 upregulated typical ferroptosis. Further studies should be performed on the regulatory roles of p53 to unmask its possible clinical applications in the management of osteosarcoma.
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Affiliation(s)
| | - Su Pan
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, China
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28
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Liu X, Tuerxun H, Li Y, Li Y, He Y, Zhao Y. Ferroptosis: Reviewing CRC with the Third Eye. J Inflamm Res 2022; 15:6801-6812. [PMID: 36575747 PMCID: PMC9790162 DOI: 10.2147/jir.s389290] [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: 09/14/2022] [Accepted: 11/08/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) has been one of the most common cancers and maintains the second-highest incidence and mortality rates among all cancers. The high risk of recurrence and metastasis and poor survival are still huge challenges in CRC therapy, in which the discovery of ferroptosis provides a novel perspective. It has been ten years since a unique type of regulated cell death driven by iron accumulation and lipid peroxidation was proposed and named ferroptosis. During the past decade, there have been multiple pieces of evidence suggesting that ferroptosis participates in the pathophysiological processes during disease progression. In this review, we describe ferroptosis as an imbalance of oxidant systems and anti-oxidants which results in lipid peroxidation, membrane damage, and finally cell death. We elaborate on the mechanisms of ferroptosis and systematically summarize recent studies on the regulatory pathways of ferroptosis in CRC from various perspectives, ranging from encoding genes, noncoding RNAs to regulatory proteins. Finally, we discuss the potential therapeutic role of ferroptosis in CRC treatments.
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Affiliation(s)
- Xingyu Liu
- Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Halahati Tuerxun
- Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Yawen Li
- Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Yaping Li
- Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Yuanyuan He
- Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China
| | - Yuguang Zhao
- Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China,Correspondence: Yuguang Zhao, Cancer Center, the First Hospital of Jilin University, Changchun, People’s Republic of China, Email
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29
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Han X, Du J, Shi D, Li L, Li D, Zhang K, Lin S, Zhu J, Huang Z, Zhou Y, Fang Z. Improving Reporter Gene Assay Methodology for Evaluating the Ability of Compounds to Restore P53 Activity. Int J Mol Sci 2022; 23:ijms232213867. [PMID: 36430341 PMCID: PMC9694221 DOI: 10.3390/ijms232213867] [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: 08/04/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 11/12/2022] Open
Abstract
Tumor suppressor protein P53 induces cycle arrest and apoptosis by mediating the transcriptional expression of its target genes. Mutations causing conformational abnormalities and post-translational modifications that promote degradation are the main reasons for the loss of P53 function in tumor cells. Reporter gene assays that can scientifically reflect the biological function can help discover the mechanism and therapeutic strategies that restore P53 function. In the reporter gene system of this work, tetracycline-inducible expression of wild-type P53 was used to provide a fully activated state as a 100% activity reference for the objective measurement of biological function. It was confirmed by RT-qPCR, cell viability assay, immunofluorescence, and Western blot analysis that the above-mentioned reporter gene system could correctly reflect the differences in biological activity between the wild-type and mutants. After that, the system was tentatively used for related mechanism research and compound activity evaluation. Through the tetracycline-induced co-expression of wild-type P53 and mutant P53 in exact proportion, it was observed that the response modes of typical transcriptional response elements (TREs) to dominant negative P53 mutation effect were not exactly the same. Compared to the relative multiple-to-solvent control, the activity percentage relative to the 100% activity reference of wild-type P53 can better reflect the actual influence of the so-called P53 mutant reactivator. Similarly, relative to the 100% activity reference, it can objectively reflect the biological effects caused by the inhibitor of P53 negative factors, such as MDM2. In conclusion, this study provides a 100% activity reference and a reliable calculation model for relevant basic research and drug development.
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Affiliation(s)
- Xinle Han
- Biomedical Research Institute, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
- Department of Pathology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jun Du
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dandan Shi
- Shenzhen Chipscreen Biosciences Co., Ltd., Shenzhen Hi-Tech Industrial Park, Shenzhen 518057, China
| | - Lingjie Li
- Shenzhen Chipscreen Biosciences Co., Ltd., Shenzhen Hi-Tech Industrial Park, Shenzhen 518057, China
| | - Dandan Li
- Shenzhen Chipscreen Biosciences Co., Ltd., Shenzhen Hi-Tech Industrial Park, Shenzhen 518057, China
| | - Kun Zhang
- Shenzhen Chipscreen Biosciences Co., Ltd., Shenzhen Hi-Tech Industrial Park, Shenzhen 518057, China
| | - Suwen Lin
- Biomedical Research Institute, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
| | - Jingzhong Zhu
- Shenzhen Chipscreen Biosciences Co., Ltd., Shenzhen Hi-Tech Industrial Park, Shenzhen 518057, China
| | - Zoufang Huang
- Ganzhou Key Laboratory of Hematology, Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - You Zhou
- Shenzhen Chipscreen Biosciences Co., Ltd., Shenzhen Hi-Tech Industrial Park, Shenzhen 518057, China
- Correspondence: (Y.Z.); (Z.F.)
| | - Zhengyu Fang
- Biomedical Research Institute, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Correspondence: (Y.Z.); (Z.F.)
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30
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Wei Z, Xie Y, Wei M, Zhao H, Ren K, Feng Q, Xu Y. New insights in ferroptosis: Potential therapeutic targets for the treatment of ischemic stroke. Front Pharmacol 2022; 13:1020918. [PMID: 36425577 PMCID: PMC9679292 DOI: 10.3389/fphar.2022.1020918] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/26/2022] [Indexed: 10/22/2023] Open
Abstract
Stroke is a common disease in clinical practice, which seriously endangers people's physical and mental health. The neurovascular unit (NVU) plays a key role in the occurrence and development of ischemic stroke. Different from other classical types of cell death such as apoptosis, necrosis, autophagy, and pyroptosis, ferroptosis is an iron-dependent lipid peroxidation-driven new form of cell death. Interestingly, the function of NVU and stroke development can be regulated by activating or inhibiting ferroptosis. This review systematically describes the NVU in ischemic stroke, provides a comprehensive overview of the regulatory mechanisms and key regulators of ferroptosis, and uncovers the role of ferroptosis in the NVU and the progression of ischemic stroke. We further discuss the latest progress in the intervention of ferroptosis as a therapeutic target for ischemic stroke and summarize the research progress and regulatory mechanism of ferroptosis inhibitors on stroke. In conclusion, ferroptosis, as a new form of cell death, plays a key role in ischemic stroke and is expected to become a new therapeutic target for this disease.
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Affiliation(s)
- Ziqing Wei
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi Xie
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingze Wei
- The Second Clinical Medical College, Harbin Medical University, Harbin, China
| | - Huijuan Zhao
- Henan International Joint Laboratory of Thrombosis and Hemostasis, Basic Medical College, Henan University of Science and Technology, Luoyang, China
| | - Kaidi Ren
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
- Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Qi Feng
- Research Institute of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Ferroptosis, a Rising Force against Renal Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7686956. [PMID: 36275899 PMCID: PMC9581688 DOI: 10.1155/2022/7686956] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/11/2022] [Indexed: 11/18/2022]
Abstract
Ferroptosis is a type of programmed cell death characterized by iron overload, oxidative stress, imbalance in lipid repair, and mitochondria-specific pathological manifestations. Growing number of molecular mechanisms and signaling pathways have been found to be involved in ferroptosis progression, including iron metabolism, amino acid metabolism, lipid metabolism, and energy metabolism. It is worth noting that ferroptosis is involved in the progression of fibrotic diseases such as liver cirrhosis, cardiomyopathy, and idiopathic pulmonary fibrosis, and inhibition of ferroptosis has acquired beneficial outcomes in rodent models, while studies on ferroptosis and renal fibrosis remains limited. Recent studies have revealed that targeting ferroptosis can effectively mitigate chronic kidney injury and renal fibrosis. Moreover, myofibroblasts suffer from ferroptosis during fiber and extracellular matrix deposition in the fibrotic cascade reaction and pharmacological modulation of ferroptosis shows great therapeutic effect on renal fibrosis. Here, we summarize the latest molecular mechanisms of ferroptosis from high-quality studies and review its therapeutic potential in renal fibrosis.
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Pan B, Li Y, Xu Z, Miao Y, Yin H, Kong Y, Zhang X, Liang J, Xia Y, Wang L, Li J, Wu J, Xu W. Identifying a novel ferroptosis-related prognostic score for predicting prognosis in chronic lymphocytic leukemia. Front Immunol 2022; 13:962000. [PMID: 36275721 PMCID: PMC9582233 DOI: 10.3389/fimmu.2022.962000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Background Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Although the treatment landscape for CLL is rapidly evolving, there are still some patients who develop drug resistance or disease refractory. Ferroptosis is a type of lipid peroxidation–induced cell death and has been suggested to have prognostic value in several cancers. Our research aims to build a prognostic model to improve risk stratification in CLL patients and facilitate more accurate assessment for clinical management. Methods The differentially expressed ferroptosis-related genes (FRGs) in CLL were filtered through univariate Cox regression analysis based on public databases. Least absolute shrinkage and selection operator (LASSO) Cox algorithms were performed to construct a prognostic risk model. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were performed to estimate the immune infiltration score and immune-related pathways. A total of 36 CLL patients in our center were enrolled in this study as a validation cohort. Moreover, a nomogram model was established to predict the prognosis. Results A total of 15 differentially expressed FRGs with prognostic significance were screened out. After minimizing the potential risk of overfitting, we constructed a novel ferroptosis-related prognostic score (FPS) model with nine FRGs (AKR1C3, BECN1, CAV1, CDKN2A, CXCL2, JDP2, SIRT1, SLC1A5, and SP1) and stratified patients into low- and high-risk groups. Kaplan–Meier analysis showed that patients with high FPS had worse overall survival (OS) (P<0.0001) and treatment-free survival (TFS) (P<0.0001). ROC curves evaluated the prognostic prediction ability of the FPS model. Additionally, the immune cell types and immune-related pathways were correlated with the risk scores in CLL patients. In the validation cohort, the results confirmed that the high-risk group was related to worse OS (P<0.0001), progress-free survival (PFS) (P=0.0140), and TFS (P=0.0072). In the multivariate analysis, only FPS (P=0.011) and CLL-IPI (P=0.010) were independent risk indicators for OS. Furthermore, we established a nomogram including FPS and CLL-IPI that could strongly and reliably predict individual prognosis. Conclusion A novel FPS model can be used in CLL for prognostic prediction. The model index may also facilitate the development of new clinical ferroptosis-targeted therapies in patients with CLL.
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Babamohamadi M, Babaei E, Ahmed Salih B, Babamohammadi M, Jalal Azeez H, Othman G. Recent findings on the role of wild-type and mutant p53 in cancer development and therapy. Front Mol Biosci 2022; 9:903075. [PMID: 36225257 PMCID: PMC9549909 DOI: 10.3389/fmolb.2022.903075] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 08/19/2022] [Indexed: 11/13/2022] Open
Abstract
The p53 protein is a tumor suppressor encoded by the TP53 gene and consists of 393 amino acids with four main functional domains. This protein responds to various cellular stresses to regulate the expression of target genes, thereby causing DNA repair, cell cycle arrest, apoptosis, metabolic changes, and aging. Mutations in the TP53 gene and the functions of the wild-type p53 protein (wtp53) have been linked to various human cancers. Eight TP53 gene mutations are located in codons, constituting 28% of all p53 mutations. The p53 can be used as a biomarker for tumor progression and an excellent target for designing cancer treatment strategies. In wild-type p53-carrying cancers, abnormal signaling of the p53 pathway usually occurs due to other unusual settings, such as high MDM2 expression. These differences between cancer cell p53 and normal cells have made p53 one of the most important targets for cancer treatment. In this review, we have dealt with various issues, such as the relative contribution of wild-type p53 loss of function, including transactivation-dependent and transactivation-independent activities in oncogenic processes and their role in cancer development. We also discuss the role of p53 in the process of ferroptosis and its targeting in cancer treatment. Finally, we focus on p53-related drug delivery systems and investigate the challenges and solutions.
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Affiliation(s)
- Mehregan Babamohamadi
- Department of Biology, School of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Esmaeil Babaei
- Department of Biology, School of Natural Sciences, University of Tabriz, Tabriz, Iran
- Interfaculty Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany
- *Correspondence: Esmaeil Babaei,
| | - Burhan Ahmed Salih
- Department of Medical Laboratory Technology, Erbil Health and Medical Technical College, Erbil Polytechnic University, Erbil, Iraq
- Department of Medical Laboratory Technology, AlQalam University College, Kirkuk, Iraq
| | - Mahshid Babamohammadi
- Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hewa Jalal Azeez
- Department of Biology, School of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Goran Othman
- Department of Medical Laboratory Technology, Erbil Health and Medical Technical College, Erbil Polytechnic University, Erbil, Iraq
- Department of Medical Laboratory Technology, AlQalam University College, Kirkuk, Iraq
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Exploring the Ferroptosis Mechanism of Zhilong Huoxue Tongyu Capsule for the Treatment of Intracerebral Hemorrhage Based on Network Pharmacology and In Vivo Validation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5033135. [PMID: 36199551 PMCID: PMC9527400 DOI: 10.1155/2022/5033135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/03/2022] [Accepted: 07/01/2022] [Indexed: 11/17/2022]
Abstract
Objective. The purpose of this study is to explore the mechanism of the Zhilong Huoxue Tongyu (ZL) capsule in the treatment of intracerebral hemorrhage (ICH) via targeting ferroptosis based on network pharmacology. Methods. The active ingredients and related key targets of the ZL capsule were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were also performed. Finally, identified targets were validated in an in-vivo model of ICH. Results. A total of 30 active ingredients and 33 intersecting targets were identified through a TCMSP database search. Ingredients-Targets-Pathways network was constructed to filter out the key targets according to the degree value. TP53 was selected as the key target. The in-vivo validation studies demonstrated that TP53 was down-regulated and GPX4 was upregulated in rats following ZL capsule treatment. Conclusions. It is concluded that the ZL capsule could alleviate ICH in a muti-target and multi-pathway manner. ZL capsule could alleviate ICH by inhibiting ferroptosis, and TP53 is identified to be the potential target. Further research is needed to clarify the detailed anti-ferroptotic mechanism of the ZL capsule.
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Shi J, Yang N, Han M, Qiu C. Emerging roles of ferroptosis in glioma. Front Oncol 2022; 12:993316. [PMID: 36072803 PMCID: PMC9441765 DOI: 10.3389/fonc.2022.993316] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 07/28/2022] [Indexed: 11/27/2022] Open
Abstract
Glioma is the most common primary malignant tumor in the central nervous system, and directly affects the quality of life and cognitive function of patients. Ferroptosis, is a new form of regulated cell death characterized by iron-dependent lipid peroxidation. Ferroptosis is mainly due to redox imbalance and involves multiple intracellular biology processes, such as iron metabolism, lipid metabolism, and antioxidants synthesis. Induction of ferroptosis could be a new target for glioma treatment, and ferroptosis-related processes are associated with chemoresistance and radioresistance in glioma. In the present review, we provide the characteristics, key regulators and pathways of ferroptosis and the crosstalk between ferroptosis and other programmed cell death in glioma, we also proposed the application and prospect of ferroptosis in the treatment of glioma.
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Affiliation(s)
- Jiaqi Shi
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Ning Yang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, China
| | - Mingzhi Han
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chen Qiu
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Chen Qiu,
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Yu R, Zhou Y, Shi S, Wang X, Huang S, Ren Y. Icariside II induces ferroptosis in renal cell carcinoma cells by regulating the miR-324-3p/GPX4 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 102:154182. [PMID: 35636172 DOI: 10.1016/j.phymed.2022.154182] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 05/04/2022] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
Icariside II (ICS II) is an active flavonoid having anti-tumor properties. However, the role of ICS II in renal cell carcinoma (RCC) and its underlying mechanisms have not been investigated to date. In this study, we demonstrated that ICS II inhibited proliferation, migration, and invasion of RCC cells. Furthermore, ferroptosis, a novel form of cell death, induced in RCC cells by ICS II, accompanied by accumulation of Fe2+, MDA (lipid peroxidation), and ROS (reactive oxygen species), and reduced GSH levels. The underlying mechanism was found to be the downregulation of GPX4, independent of p53, that occurs during ICS II-induced ferroptosis. Overexpression of GPX4 reversed the ferroptosis induced by ICS II. Moreover, ICS II treatment resulted in the upregulation of miR-324-3p, which directly targets GPX4. Overall, our results suggested that ICS II-induced ferroptosis via the miR-324-3p/GPX4 axis in RCC cells could be a promising therapeutic agent for RCC.
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Affiliation(s)
- Rui Yu
- Department of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Youfeng Zhou
- Department of Urologic Surgery, Ningbo Urology and Nephrology Hospital, Ningbo Yinzhou NO2. Hospital, Ningbo, China
| | - Shufeng Shi
- Department of Urologic Surgery, Ningbo Urology and Nephrology Hospital, Ningbo Yinzhou NO2. Hospital, Ningbo, China
| | - Xue Wang
- Department of Urologic Surgery, Ningbo Urology and Nephrology Hospital, Ningbo Yinzhou NO2. Hospital, Ningbo, China
| | - Shuaishuai Huang
- Department of Urologic Surgery, Ningbo Urology and Nephrology Hospital, Ningbo Yinzhou NO2. Hospital, Ningbo, China
| | - Yu Ren
- Department of Urologic Surgery, Ningbo Urology and Nephrology Hospital, Ningbo Yinzhou NO2. Hospital, Ningbo, China.
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Wang J, Yang W, He X, Zhang Z, Zheng X. Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor. Front Bioeng Biotechnol 2022; 10:929536. [PMID: 35837547 PMCID: PMC9273839 DOI: 10.3389/fbioe.2022.929536] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/17/2022] [Indexed: 11/22/2022] Open
Abstract
Inducing lipid peroxidation and subsequent ferroptosis in cancer cells provides a potential approach for anticancer therapy. However, the clinical translation of such therapeutic agents is often hampered by ferroptosis resistance and acquired drug tolerance in host cells. Emerging nanoplatform-based cascade engineering and ferroptosis sensitization by p53 provides a viable rescue strategy. Herein, a metallo-organic supramolecular (Nano-PMI@CeO2) toward p53 restoration and subsequent synergistic ferroptosis is constructed, in which the radical generating module-CeO2 nanoparticles act as the core, and p53-activator peptide (PMI)-gold precursor polymer is in situ reduced and assembled on the CeO2 surface as the shell. As expected, Nano-PMI@CeO2 effectively reactivated the p53 signaling pathway in vitro and in vivo, thereby downregulating its downstream gene GPX4. As a result, Nano-PMI@CeO2 significantly inhibited tumor progression in the lung cancer allograft model through p53 restoration and sensitized ferroptosis, while maintaining favorable biosafety. Collectively, this work develops a tumor therapeutic with dual functions of inducing ferroptosis and activating p53, demonstrating a potentially viable therapeutic paradigm for sensitizing ferroptosis via p53 activation. It also suggests that metallo-organic supramolecule holds great promise in transforming nanomedicine and treating human diseases.
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Affiliation(s)
- Jingmei Wang
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenguang Yang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Talent Highland, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, China
| | - Xinyuan He
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhang Zhang
- General Surgery Department, Tang Du Hospital, The Fourth Military Medical University, Xi’an, China
- *Correspondence: Zhang Zhang, ; Xiaoqiang Zheng,
| | - Xiaoqiang Zheng
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- *Correspondence: Zhang Zhang, ; Xiaoqiang Zheng,
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Zhang L, Hou N, Chen B, Kan C, Han F, Zhang J, Sun X. Post-Translational Modifications of p53 in Ferroptosis: Novel Pharmacological Targets for Cancer Therapy. Front Pharmacol 2022; 13:908772. [PMID: 35685623 PMCID: PMC9171069 DOI: 10.3389/fphar.2022.908772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/10/2022] [Indexed: 12/21/2022] Open
Abstract
The tumor suppressor p53 is a well-known cellular guardian of genomic integrity that blocks cell cycle progression or induces apoptosis upon exposure to cellular stresses. However, it is unclear how the remaining activities of p53 are regulated after the abrogation of these routine activities. Ferroptosis is a form of iron- and lipid-peroxide-mediated cell death; it is particularly important in p53-mediated carcinogenesis and corresponding cancer prevention. Post-translational modifications have clear impacts on the tumor suppressor function of p53. Here, we review the roles of post-translational modifications in p53-mediated ferroptosis, which promotes the elimination of tumor cells. A thorough understanding of the p53 functional network will be extremely useful in future strategies to identify pharmacological targets for cancer therapy.
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Affiliation(s)
- Le Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Bing Chen
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Jingwen Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- *Correspondence: Jingwen Zhang, ; Xiaodong Sun,
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- *Correspondence: Jingwen Zhang, ; Xiaodong Sun,
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