铁死亡在心血管疾病中作用机制的研究进展
Advances in Mechanisms of Ferroptosis in Cardiovascular Disease
DOI: 10.12677/acm.2025.1541076, PDF,   
作者: 李 婷, 徐建红*：浙江大学医学院附属第四医院国际医学院，国际健康医学研究院麻醉科，浙江 义乌；张冯江*：浙江大学医学院附属第二医院麻醉科，浙江 杭州
关键词: 铁死亡；心血管疾病；脂质过氧化；Ferroptosis； Cardiovascular Disease； Lipid Peroxidation
摘要: 铁死亡是不同于细胞凋亡，坏死的新型细胞死亡方式。研究表明铁死亡参与心血管疾病的发生发展，铁死亡在心肌病，心肌梗死，缺血再灌注损伤和心力衰竭中起关键作用。中国患有心血管疾病的总人数超过了肿瘤和其他慢性病，疾病负担重。然而铁死亡在心血管疾病中的作用机制，治疗靶点仍需进一步阐明。本文概述了铁死亡的分子机制及其在心血管疾病中的作用，强调靶向铁死亡可能是未来心血管疾病的潜在治疗策略。
Abstract: Ferroptosis is a novel form of cell death distinct from apoptosis and necrosis. Studies have shown that Ferroptosis is involved in the development of cardiovascular disease and plays a key role in cardiomyopathy, myocardial infarction, ischemia-reperfusion injury and heart failure. The total number of people suffering from cardiovascular disease in China exceeds that of oncology and other chronic diseases, and the burden of disease is high. However, the mechanism of Ferroptosis in cardiovascular diseases and therapeutic targets still need to be further elucidated. This article provides an overview of the molecular mechanisms of Ferroptosis and its role in cardiovascular disease, emphasising that targeting Ferroptosis may be a potential therapeutic strategy for cardiovascular disease.
文章引用：李婷, 张冯江, 徐建红. 铁死亡在心血管疾病中作用机制的研究进展[J]. 临床医学进展, 2025, 15(4): 1433-1440. https://doi.org/10.12677/acm.2025.1541076

参考文献

[1] Xu, C., Ou, E., Li, Z., Chen, Z., Jia, Q., Xu, X., et al. (2022) Synthesis and in Vivo Evaluation of New Steviol Derivatives That Protect against Cardiomyopathy by Inhibiting Ferroptosis. Bioorganic Chemistry, 129, Article ID: 106142. [Google Scholar] [CrossRef] [PubMed]
[2] Zhang, T., Deng, W., Deng, Y., Liu, Y., Xiao, S., Luo, Y., et al. (2023) Mechanisms of Ferroptosis Regulating Oxidative Stress and Energy Metabolism in Myocardial Ischemia-Reperfusion Injury and a Novel Perspective of Natural Plant Active Ingredients for Its Treatment. Biomedicine & Pharmacotherapy, 165, Article ID: 114706. [Google Scholar] [CrossRef] [PubMed]
[3] Wilcox, N.S., Amit, U., Reibel, J.B., Berlin, E., Howell, K. and Ky, B. (2024) Cardiovascular Disease and Cancer: Shared Risk Factors and Mechanisms. Nature Reviews Cardiology, 21, 617-631. [Google Scholar] [CrossRef] [PubMed]
[4] Ju, J., Li, X., Zhao, X., Li, F., Wang, S., Wang, K., et al. (2023) Circular RNA FEACR Inhibits Ferroptosis and Alleviates Myocardial Ischemia/reperfusion Injury by Interacting with NAMPT. Journal of Biomedical Science, 30, Article No. 45. [Google Scholar] [CrossRef] [PubMed]
[5] Li, N., Jiang, W., Wang, W., Xiong, R., Wu, X. and Geng, Q. (2021) Ferroptosis and Its Emerging Roles in Cardiovascular Diseases. Pharmacological Research, 166, Article ID: 105466. [Google Scholar] [CrossRef] [PubMed]
[6] Li, D., Pi, W., Sun, Z., Liu, X. and Jiang, J. (2022) Ferroptosis and Its Role in Cardiomyopathy. Biomedicine & Pharmacotherapy, 153, Article ID: 113279. [Google Scholar] [CrossRef] [PubMed]
[7] Xie, L., Fefelova, N., Pamarthi, S.H. and Gwathmey, J.K. (2022) Molecular Mechanisms of Ferroptosis and Relevance to Cardiovascular Disease. Cells, 11, Article 2726. [Google Scholar] [CrossRef] [PubMed]
[8] Guo, Y., Lu, C., Hu, K., Cai, C. and Wang, W. (2022) Ferroptosis in Cardiovascular Diseases: Current Status, Challenges, and Future Perspectives. Biomolecules, 12, Article 390. [Google Scholar] [CrossRef] [PubMed]
[9] Ahola, S., Rivera Mejías, P., Hermans, S., Chandragiri, S., Giavalisco, P., Nolte, H., et al. (2022) OMA1-Mediated Integrated Stress Response Protects against Ferroptosis in Mitochondrial Cardiomyopathy. Cell Metabolism, 34, 1875-1891.e7. [Google Scholar] [CrossRef] [PubMed]
[10] Fang, X., Wang, H., Han, D., Xie, E., Yang, X., Wei, J., et al. (2019) Ferroptosis as a Target for Protection against Cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 116, 2672-2680. [Google Scholar] [CrossRef] [PubMed]
[11] Komai, K., Kawasaki, N.K., Higa, J.K. and Matsui, T. (2022) The Role of Ferroptosis in Adverse Left Ventricular Remodeling Following Acute Myocardial Infarction. Cells, 11, Article 1399. [Google Scholar] [CrossRef] [PubMed]
[12] Xiang, Q., Yi, X., Zhu, X.H., Wei, X. and Jiang, D.S. (2023) Regulated Cell Death in Myocardial Ischemia-Reperfusion Injury. Trends in Endocrinology & Metabolism, 35, 219-234.
[13] Zhang, K., Tian, X., Li, W. and Hao, L. (2023) Ferroptosis in Cardiac Hypertrophy and Heart Failure. Biomedicine & Pharmacotherapy, 168, Article ID: 115765. [Google Scholar] [CrossRef] [PubMed]
[14] Wu, X., Li, Y., Zhang, S. and Zhou, X. (2021) Ferroptosis as a Novel Therapeutic Target for Cardiovascular Disease. Theranostics, 11, 3052-3059. [Google Scholar] [CrossRef] [PubMed]
[15] Chen, Y., Li, X., Wang, S., Miao, R. and Zhong, J. (2023) Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases. Nutrients, 15, Article 591. [Google Scholar] [CrossRef] [PubMed]
[16] Fang, X., Cai, Z., Wang, H., Han, D., Cheng, Q., Zhang, P., et al. (2020) Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis. Circulation Research, 127, 486-501. [Google Scholar] [CrossRef] [PubMed]
[17] Duan, J., Lin, X., Xu, F., Shan, S., Guo, B., Li, F., et al. (2021) Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization? Frontiers in Cell and Developmental Biology, 9, Article 701788. [Google Scholar] [CrossRef] [PubMed]
[18] Fang, X., Ardehali, H., Min, J. and Wang, F. (2022) The Molecular and Metabolic Landscape of Iron and Ferroptosis in Cardiovascular Disease. Nature Reviews Cardiology, 20, 7-23. [Google Scholar] [CrossRef] [PubMed]
[19] Zhang, Y., Xin, L., Xiang, M., Shang, C., Wang, Y., Wang, Y., et al. (2022) The Molecular Mechanisms of Ferroptosis and Its Role in Cardiovascular Disease. Biomedicine & Pharmacotherapy, 145, Article ID: 112423. [Google Scholar] [CrossRef] [PubMed]
[20] Fratta Pasini, A.M., Stranieri, C., Busti, F., Di Leo, E.G., Girelli, D. and Cominacini, L. (2023) New Insights into the Role of Ferroptosis in Cardiovascular Diseases. Cells, 12, Article 867. [Google Scholar] [CrossRef] [PubMed]
[21] Han, X., Zhang, J., Liu, J., Wang, H., Du, F., Zeng, X., et al. (2022) Targeting Ferroptosis: A Novel Insight against Myocardial Infarction and Ischemia-Reperfusion Injuries. Apoptosis, 28, 108-123. [Google Scholar] [CrossRef] [PubMed]
[22] Sun, H., Chen, D., Xin, W., Ren, L., LI, Q. and Han, X. (2023) Targeting Ferroptosis as a Promising Therapeutic Strategy to Treat Cardiomyopathy. Frontiers in Pharmacology, 14, Article 1146651. [Google Scholar] [CrossRef] [PubMed]
[23] Chen, W., Zhang, Y., Wang, Z., Tan, M., Lin, J., Qian, X., et al. (2023) Dapagliflozin Alleviates Myocardial Ischemia/Reperfusion Injury by Reducing Ferroptosis via MAPK Signaling Inhibition. Frontiers in Pharmacology, 14, Article 1078205. [Google Scholar] [CrossRef] [PubMed]
[24] Ferdinandy, P., Andreadou, I., Baxter, G.F., Bøtker, H.E., Davidson, S.M., Dobrev, D., et al. (2023) Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning. Pharmacological Reviews, 75, 159-216. [Google Scholar] [CrossRef] [PubMed]
[25] Ma, X., Liu, J., Liu, C., Sun, W., Duan, W., Wang, G., et al. (2022) ALOX15-launched PUFA-Phospholipids Peroxidation Increases the Susceptibility of Ferroptosis in Ischemia-Induced Myocardial Damage. Signal Transduction and Targeted Therapy, 7, Article No. 288. [Google Scholar] [CrossRef] [PubMed]
[26] Moon, B.F., Iyer, S.K., Hwuang, E., Solomon, M.P., Hall, A.T., Kumar, R., et al. (2020) Iron Imaging in Myocardial Infarction Reperfusion Injury. Nature Communications, 11, Article No. 3273. [Google Scholar] [CrossRef] [PubMed]
[27] Ye, J., Lyu, T., Li, L., Liu, Y., Zhang, H., Wang, X., et al. (2023) Ginsenoside Re Attenuates Myocardial Ischemia/Reperfusion Induced Ferroptosis via miR-144-3p/SLC7A11. Phytomedicine, 113, Article ID: 154681. [Google Scholar] [CrossRef] [PubMed]
[28] Lin, J., Yang, K., Ting, P., Luo, Y., Lin, D., Wang, Y., et al. (2021) Gossypol Acetic Acid Attenuates Cardiac Ischemia/Reperfusion Injury in Rats via an Antiferroptotic Mechanism. Biomolecules, 11, Article 1667. [Google Scholar] [CrossRef] [PubMed]
[29] Huang, Q., Tian, L., Zhang, Y., Qiu, Z., Lei, S. and Xia, Z. (2023) Nobiletin Alleviates Myocardial Ischemia-Reperfusion Injury via Ferroptosis in Rats with Type-2 Diabetes Mellitus. Biomedicine & Pharmacotherapy, 163, Article ID: 114795. [Google Scholar] [CrossRef] [PubMed]
[30] Qian, W., Liu, D., Han, Y., Liu, M., Liu, B., Ji, Q., et al. (2023) Cyclosporine A-Loaded Apoferritin Alleviates Myocardial Ischemia-Reperfusion Injury by Simultaneously Blocking Ferroptosis and Apoptosis of Cardiomyocytes. Acta Biomaterialia, 160, 265-280. [Google Scholar] [CrossRef] [PubMed]
[31] Zhang, Y., Ren, X., Wang, Y., Chen, D., Jiang, L., Li, X., et al. (2021) Targeting Ferroptosis by Polydopamine Nanoparticles Protects Heart against Ischemia/reperfusion Injury. ACS Applied Materials & Interfaces, 13, 53671-53682. [Google Scholar] [CrossRef] [PubMed]
[32] Ravingerová, T., Kindernay, L., Barteková, M., Ferko, M., Adameová, A., Zohdi, V., et al. (2020) The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection. International Journal of Molecular Sciences, 21, Article 7889. [Google Scholar] [CrossRef] [PubMed]
[33] Ichihara, G., Katsumata, Y., Sugiura, Y., Matsuoka, Y., Maeda, R., Endo, J., et al. (2023) MRP1-Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis after Ischemia-Reperfusion. Circulation Research, 133, 861-876. [Google Scholar] [CrossRef] [PubMed]
[34] Davidson, S.M., Ferdinandy, P., Andreadou, I., Bøtker, H.E., Heusch, G., Ibáñez, B., et al. (2019) Multitarget Strategies to Reduce Myocardial Ischemia/reperfusion Injury. Journal of the American College of Cardiology, 73, 89-99. [Google Scholar] [CrossRef] [PubMed]
[35] Li, K., Liu, P., Han, L., Tian, J., Zheng, Z., Sha, M., et al. (2024) Elucidating Ferroptosis Mechanisms in Heart Failure through Transcriptomics, Single-Cell Sequencing, and Experimental Validation. Cellular Signalling, 124, Article ID: 111416. [Google Scholar] [CrossRef] [PubMed]
[36] Xiong, Y., Liu, X., Jiang, L., Hao, T., Wang, Y. and Li, T. (2024) Inhibition of Ferroptosis Reverses Heart Failure with Preserved Ejection Fraction in Mice. Journal of Translational Medicine, 22, Article No. 199. [Google Scholar] [CrossRef] [PubMed]
[37] Bi, X., Wu, X., Chen, J., Li, X., Lin, Y., Yu, Y., et al. (2024) Characterization of Ferroptosis-Triggered Pyroptotic Signaling in Heart Failure. Signal Transduction and Targeted Therapy, 9, Article No. 257. [Google Scholar] [CrossRef] [PubMed]
[38] Packer, M. (2023) Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure. JACC: Heart Failure, 11, 106-114. [Google Scholar] [CrossRef] [PubMed]
[39] Yang, X., Kawasaki, N.K., Min, J., Matsui, T. and Wang, F. (2022) Ferroptosis in Heart Failure. Journal of Molecular and Cellular Cardiology, 173, 141-153. [Google Scholar] [CrossRef] [PubMed]
[40] Zhang, W., Qian, S., Tang, B., Kang, P., Zhang, H. and Shi, C. (2023) Resveratrol Inhibits Ferroptosis and Decelerates Heart Failure Progression via Sirt1/p53 Pathway Activation. Journal of Cellular and Molecular Medicine, 27, 3075-3089. [Google Scholar] [CrossRef] [PubMed]
[41] Su, H., Cantrell, A.C., Chen, J., Gu, W. and Zeng, H. (2023) SIRT3 Deficiency Enhances Ferroptosis and Promotes Cardiac Fibrosis via P53 Acetylation. Cells, 12, Article 1428. [Google Scholar] [CrossRef] [PubMed]
[42] Kobashigawa, J., Zuckermann, A., Macdonald, P., Leprince, P., Esmailian, F., Luu, M., et al. (2014) Report from a Consensus Conference on Primary Graft Dysfunction after Cardiac Transplantation. The Journal of Heart and Lung Transplantation, 33, 327-340. [Google Scholar] [CrossRef] [PubMed]
[43] Li, W., Feng, G., Gauthier, J.M., Lokshina, I., Higashikubo, R., Evans, S., et al. (2019) Ferroptotic Cell Death and TLR4/Trif Signaling Initiate Neutrophil Recruitment after Heart Transplantation. Journal of Clinical Investigation, 129, 2293-2304. [Google Scholar] [CrossRef] [PubMed]
[44] Jin, E., Jo, Y., Wei, S., Rizzo, M., Ryu, D. and Gariani, K. (2024) Ferroptosis and Iron Metabolism in Diabetes: Pathogenesis, Associated Complications, and Therapeutic Implications. Frontiers in Endocrinology, 15, Article 1447148. [Google Scholar] [CrossRef] [PubMed]
[45] Wei, J., Zhao, Y., Liang, H., Du, W. and Wang, L. (2022) Preliminary Evidence for the Presence of Multiple Forms of Cell Death in Diabetes Cardiomyopathy. Acta Pharmaceutica Sinica B, 12, 1-17. [Google Scholar] [CrossRef] [PubMed]
[46] Cheng, Z., Fang, T., Huang, J., Guo, Y., Alam, M. and Qian, H. (2021) Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment. Frontiers in Cardiovascular Medicine, 8, Article 722340. [Google Scholar] [CrossRef] [PubMed]
[47] Wang, Z., Xia, Q., Su, W., Cao, M., Sun, Y., Zhang, M., et al. (2022) Exploring the Communal Pathogenesis, Ferroptosis Mechanism, and Potential Therapeutic Targets of Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy via a Microarray Data Analysis. Frontiers in Cardiovascular Medicine, 9, Article 824756. [Google Scholar] [CrossRef] [PubMed]
[48] Oudit, G.Y., Sun, H., Trivieri, M.G., Koch, S.E., Dawood, F., Ackerley, C., et al. (2003) L-Type Ca2+ Channels Provide a Major Pathway for Iron Entry into Cardiomyocytes in Iron-Overload Cardiomyopathy. Nature Medicine, 9, 1187-1194. [Google Scholar] [CrossRef] [PubMed]
[49] Link, G., Pinson, A. and Hershko, C. (1985) Heart Cells in Culture: A Model of Myocardial Iron Overload and Chelation. Journal of Laboratory and Clinical Medicine, 106, 147-153.
[50] Liu, P., Zhang, Z., Cai, Y., Li, Z., Zhou, Q. and Chen, Q. (2024) Ferroptosis: Mechanisms and Role in Diabetes Mellitus and Its Complications. Ageing Research Reviews, 94, Article ID: 102201. [Google Scholar] [CrossRef] [PubMed]
[51] Tadokoro, T., Ikeda, M., Ide, T., Deguchi, H., Ikeda, S., Okabe, K., et al. (2020) Mitochondria-Dependent Ferroptosis Plays a Pivotal Role in Doxorubicin Cardiotoxicity. JCI Insight, 5, e132747. [Google Scholar] [CrossRef] [PubMed]
[52] Ta, N., Qu, C., Wu, H., Zhang, D., Sun, T., Li, Y., et al. (2022) Mitochondrial Outer Membrane Protein FUNDC2 Promotes Ferroptosis and Contributes to Doxorubicin-Induced Cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 119, e2117396119. [Google Scholar] [CrossRef] [PubMed]
[53] Wang, Y., Yan, S., Liu, X., Deng, F., Wang, P., Yang, L., et al. (2022) PRMT4 Promotes Ferroptosis to Aggravate Doxorubicin-Induced Cardiomyopathy via Inhibition of the Nrf2/GPX4 Pathway. Cell Death & Differentiation, 29, 1982-1995. [Google Scholar] [CrossRef] [PubMed]

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