铁死亡在心肌缺血再灌注损伤机制中的研究进展
Research Progress of the Mechanism of Ferroptosis in Myocardial Ischemia-Reperfusion Injury
DOI: 10.12677/acm.2025.153627, PDF,   
作者: 赵嘉璐：内蒙古医科大学鄂尔多斯临床医学院，内蒙古 鄂尔多斯；刘振兵*：鄂尔多斯市中心医院心内科，内蒙古 鄂尔多斯
关键词: 铁死亡；心肌缺血再灌注损伤；铁代谢；脂质过氧化；Ferroptosis； Myocardial Ischemia-Reperfusion Injury； Iron Metabolism； Lipid Peroxidation
摘要: 铁死亡是一种依赖于铁离子与活性氧(reactiveoxygen species, ROS)诱导的脂质过氧化物积累，进而引发的一种特殊的细胞死亡机制，是一种调节性细胞死亡的形式。近年来研究显示，其在肿瘤、心脏、肾脏、脑的缺血再灌注损伤及其他多种疾病中发挥重要作用。本文将从铁代谢、脂质代谢、氨基酸代谢等机制方面综述铁死亡在心肌缺血再灌注损伤中的研究进展。并总结了可能对心肌缺血再灌注损伤有治疗作用的抑制剂及相关靶点，旨在从铁死亡角度为治疗心肌缺血再灌注损伤提供新的防治策略。
Abstract: Ferroptosis is a special mechanism of cell death induced by the accumulation of lipid peroxides, which depends on iron ions and reactive oxygen species (ROS). It is a form of regulated cell death. In recent years, research has shown that it plays an important role in tumors, cardiac, renal, cerebral ischemia-reperfusion injury, and many other diseases. This paper reviews the research progress of ferroptosis in myocardial ischemia-reperfusion injury from the aspects of mechanisms such as iron metabolism, lipid metabolism, and amino acid metabolism. It also summarizes the inhibitors and related targets that may have a therapeutic effect on myocardial ischemia-reperfusion injury, aiming to provide new prevention and treatment strategies for myocardial ischemia-reperfusion injury from the perspective of ferroptosis.
文章引用：赵嘉璐, 刘振兵. 铁死亡在心肌缺血再灌注损伤机制中的研究进展[J]. 临床医学进展, 2025, 15(3): 384-392. https://doi.org/10.12677/acm.2025.153627

参考文献

[1] Wang, J., Liu, Y., Liu, Y., Huang, H., Roy, S., Song, Z., et al. (2023) Recent Advances in Nanomedicines for Imaging and Therapy of Myocardial Ischemia-Reperfusion Injury. Journal of Controlled Release, 353, 563-590. [Google Scholar] [CrossRef] [PubMed]
[2] Zhang, C., Yan, Y. and Luo, Q. (2024) The Molecular Mechanisms and Potential Drug Targets of Ferroptosis in Myocardial Ischemia-Reperfusion Injury. Life Sciences, 340, Article ID: 122439. [Google Scholar] [CrossRef] [PubMed]
[3] Li, J., Cao, F., Yin, H., Huang, Z., Lin, Z., Mao, N., et al. (2020) Ferroptosis: Past, Present and Future. Cell Death & Disease, 11, Article No. 88. [Google Scholar] [CrossRef] [PubMed]
[4] Sukhbaatar, N. and Weichhart, T. (2018) Iron Regulation: Macrophages in Control. Pharmaceuticals, 11, Article 137. [Google Scholar] [CrossRef] [PubMed]
[5] Du, C., Zhou, L., Qian, J., He, M., Zhang, Z., Feng, C., et al. (2021) Ultrasmall Zwitterionic Polypeptide-Coordinated Nanohybrids for Highly Efficient Cancer Photothermal Ferrotherapy. ACS Applied Materials & Interfaces, 13, 44002-44012. [Google Scholar] [CrossRef] [PubMed]
[6] 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]
[7] Lakhal-Littleton, S., Wolna, M., Carr, C.A., Miller, J.J.J., Christian, H.C., Ball, V., et al. (2015) Cardiac Ferroportin Regulates Cellular Iron Homeostasis and Is Important for Cardiac Function. Proceedings of the National Academy of Sciences, 112, 3164-3169. [Google Scholar] [CrossRef] [PubMed]
[8] Di Paola, A., Tortora, C., Argenziano, M., Marrapodi, M.M. and Rossi, F. (2022) Emerging Roles of the Iron Chelators in Inflammation. International Journal of Molecular Sciences, 23, Article 7977. [Google Scholar] [CrossRef] [PubMed]
[9] Fang, J., Kong, B., Shuai, W., Xiao, Z., Dai, C., Qin, T., et al. (2021) Ferroportin-Mediated Ferroptosis Involved in New-Onset Atrial Fibrillation with Lps-Induced Endotoxemia. European Journal of Pharmacology, 913, Article ID: 174622. [Google Scholar] [CrossRef] [PubMed]
[10] Zlatanova, I., Pinto, C., Bonnin, P., Mathieu, J.R.R., Bakker, W., Vilar, J., et al. (2019) Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair after Injury. Circulation, 139, 1530-1547. [Google Scholar] [CrossRef] [PubMed]
[11] Ghafourian, K., Shapiro, J.S., Goodman, L. and Ardehali, H. (2020) Iron and Heart Failure. JACC: Basic to Translational Science, 5, 300-313. [Google Scholar] [CrossRef] [PubMed]
[12] Jankowska, E.A., Kasztura, M., Sokolski, M., Bronisz, M., Nawrocka, S., Ole Kowska-Florek, W., et al. (2014) Iron Deficiency Defined as Depleted Iron Stores Accompanied by Unmet Cellular Iron Requirements Identifies Patients at the Highest Risk of Death after an Episode of Acute Heart Failure. European Heart Journal, 35, 2468-2476. [Google Scholar] [CrossRef] [PubMed]
[13] Yamamoto, K., Kuragano, T., Kimura, T., Nanami, M., Hasuike, Y. and Nakanishi, T. (2018) Interplay of Adipocyte and Hepatocyte: Leptin Upregulates Hepcidin. Biochemical and Biophysical Research Communications, 495, 1548-1554. [Google Scholar] [CrossRef] [PubMed]
[14] 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, 116, 2672-2680. [Google Scholar] [CrossRef] [PubMed]
[15] Jiang, L., Hickman, J.H., Wang, S. and Gu, W. (2015) Dynamic Roles of P53-Mediated Metabolic Activities in Ros-Induced Stress Responses. Cell Cycle, 14, 2881-2885. [Google Scholar] [CrossRef] [PubMed]
[16] 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]
[17] Stockwell, B.R., Friedmann Angeli, J.P., Bayir, H., Bush, A.I., Conrad, M., Dixon, S.J., et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171, 273-285. [Google Scholar] [CrossRef] [PubMed]
[18] Shi, Y., Han, L., Zhang, X., Xie, L., Pan, P. and Chen, F. (2022) Selenium Alleviates Cerebral Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Fusion and Ferroptosis. Neurochemical Research, 47, 2992-3002. [Google Scholar] [CrossRef] [PubMed]
[19] Zhang, Y., Swanda, R.V., Nie, L., Liu, X., Wang, C., Lee, H., et al. (2021) Mtorc1 Couples Cyst(e)ine Availability with GPX4 Protein Synthesis and Ferroptosis Regulation. Nature Communications, 12, Article No. 1589. [Google Scholar] [CrossRef] [PubMed]
[20] Tang, L., Luo, X., Tu, H., Chen, H., Xiong, X., Li, N., et al. (2020) Ferroptosis Occurs in Phase of Reperfusion but Not Ischemia in Rat Heart Following Ischemia or Ischemia/Reperfusion. Naunyn-Schmiedeberg’s Archives of Pharmacology, 394, 401-410. [Google Scholar] [CrossRef] [PubMed]
[21] Jelinek, A., Heyder, L., Daude, M., Plessner, M., Krippner, S., Grosse, R., et al. (2018) Mitochondrial Rescue Prevents Glutathione Peroxidase-Dependent Ferroptosis. Free Radical Biology and Medicine, 117, 45-57. [Google Scholar] [CrossRef] [PubMed]
[22] 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, 116, 2672-2680. [Google Scholar] [CrossRef] [PubMed]
[23] 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]
[24] Bochkov, V.N., Oskolkova, O.V., Birukov, K.G., Levonen, A., Binder, C.J. and Stöckl, J. (2010) Generation and Biological Activities of Oxidized Phospholipids. Antioxidants & Redox Signaling, 12, 1009-1059. [Google Scholar] [CrossRef] [PubMed]
[25] Yin, H., Xu, L. and Porter, N.A. (2011) Free Radical Lipid Peroxidation: Mechanisms and Analysis. Chemical Reviews, 111, 5944-5972. [Google Scholar] [CrossRef] [PubMed]
[26] Kuhn, H., Banthiya, S. and van Leyen, K. (2015) Mammalian Lipoxygenases and Their Biological Relevance. Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, 1851, 308-330. [Google Scholar] [CrossRef] [PubMed]
[27] Kraft, V.A.N., Bezjian, C.T., Pfeiffer, S., Ringelstetter, L., Müller, C., Zandkarimi, F., et al. (2019) GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Central Science, 6, 41-53. [Google Scholar] [CrossRef] [PubMed]
[28] Stockwell, B.R., Friedmann Angeli, J.P., Bayir, H., Bush, A.I., Conrad, M., Dixon, S.J., et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171, 273-285. [Google Scholar] [CrossRef] [PubMed]
[29] D’Oria, R., Schipani, R., Leonardini, A., Natalicchio, A., Perrini, S., Cignarelli, A., et al. (2020) The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor. Oxidative Medicine and Cellular Longevity, 2020, 1-29. [Google Scholar] [CrossRef] [PubMed]
[30] Romuk, E., Wojciechowska, C., Jacheć, W., Zemła-Woszek, A., Momot, A., Buczkowska, M., et al. (2019) Malondialdehyde and Uric Acid as Predictors of Adverse Outcome in Patients with Chronic Heart Failure. Oxidative Medicine and Cellular Longevity, 2019, 1-15. [Google Scholar] [CrossRef] [PubMed]
[31] Walter, M.F., Jacob, R.F., Jeffers, B., Ghadanfar, M.M., Preston, G.M., Buch, J., et al. (2004) Serum Levels of Thiobarbituric Acid Reactive Substances Predict Cardiovascular Events in Patients with Stable Coronary Artery Disease. Journal of the American College of Cardiology, 44, 1996-2002. [Google Scholar] [CrossRef] [PubMed]
[32] Gianazza, E., Brioschi, M., Martinez Fernandez, A., Casalnuovo, F., Altomare, A., Aldini, G., et al. (2021) Lipid Peroxidation in Atherosclerotic Cardiovascular Diseases. Antioxidants & Redox Signaling, 34, 49-98. [Google Scholar] [CrossRef] [PubMed]
[33] Zhang, Y., Tan, H., Daniels, J.D., Zandkarimi, F., Liu, H., Brown, L.M., et al. (2019) Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model. Cell Chemical Biology, 26, 623-633.e9. [Google Scholar] [CrossRef] [PubMed]
[34] Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A.J., Yang, W.S., Fridman, D.J., et al. (2007) RAS-RAF-MEK-Dependent Oxidative Cell Death Involving Voltage-Dependent Anion Channels. Nature, 447, 865-869. [Google Scholar] [CrossRef] [PubMed]
[35] Sui, X., Zhang, R., Liu, S., Duan, T., Zhai, L., Zhang, M., et al. (2018) RSL3 Drives Ferroptosis through GPX4 Inactivation and ROS Production in Colorectal Cancer. Frontiers in Pharmacology, 9, Article 1371. [Google Scholar] [CrossRef] [PubMed]
[36] Cui, Y., Zhang, Z., Zhou, X., Zhao, Z., Zhao, R., Xu, X., et al. (2021) Microglia and Macrophage Exhibit Attenuated Inflammatory Response and Ferroptosis Resistance after RSL3 Stimulation via Increasing Nrf2 Expression. Journal of Neuroinflammation, 18, Article No. 249. [Google Scholar] [CrossRef] [PubMed]
[37] Sun, Y., Berleth, N., Wu, W., Schlütermann, D., Deitersen, J., Stuhldreier, F., et al. (2021) Fin56-induced Ferroptosis Is Supported by Autophagy-Mediated GPX4 Degradation and Functions Synergistically with mTOR Inhibition to Kill Bladder Cancer Cells. Cell Death & Disease, 12, Article No. 1028. [Google Scholar] [CrossRef] [PubMed]
[38] Zhang, L., Luo, Y.L., Xiang, Y., Bai, X.Y., Qiang, R.R., Zhang, X., et al. (2024) Ferroptosis Inhibitors: Past, Present and Future. Frontiers in Pharmacology, 15, Article 1407335. [Google Scholar] [CrossRef] [PubMed]
[39] Yao, X., Zhang, Y., Fan, B., Pang, Y., Shen, W., Wang, X., et al. (2020) Neuroprotective Effect of Deferoxamine on Erastininduced Ferroptosis in Primary Cortical Neurons. Neural Regeneration Research, 15, 1539-1545. [Google Scholar] [CrossRef] [PubMed]
[40] Abdul Ghani, M.A., Ugusman, A., Latip, J. and Zainalabidin, S. (2023) Role of Terpenophenolics in Modulating Inflammation and Apoptosis in Cardiovascular Diseases: A Review. International Journal of Molecular Sciences, 24, Article 5339. [Google Scholar] [CrossRef] [PubMed]
[41] Kattamis, A. (2019) Renal Function Abnormalities and Deferasirox. The Lancet Child & Adolescent Health, 3, 2-3. [Google Scholar] [CrossRef] [PubMed]
[42] Zilka, O., Shah, R., Li, B., Friedmann Angeli, J.P., Griesser, M., Conrad, M., et al. (2017) On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Central Science, 3, 232-243. [Google Scholar] [CrossRef] [PubMed]
[43] Cai, Y., Li, X., Tan, X., Wang, P., Zhao, X., Zhang, H., et al. (2022) Vitamin D Suppresses Ferroptosis and Protects against Neonatal Hypoxic-Ischemic Encephalopathy by Activating the Nrf2/HO-1 Pathway. Translational Pediatrics, 11, 1633-1644. [Google Scholar] [CrossRef] [PubMed]
[44] Li, W., Liang, L., Liu, S., Yi, H. and Zhou, Y. (2023) FSP1: A Key Regulator of Ferroptosis. Trends in Molecular Medicine, 29, 753-764. [Google Scholar] [CrossRef] [PubMed]
[45] Dodson, M., Castro-Portuguez, R. and Zhang, D.D. (2019) NRF2 Plays a Critical Role in Mitigating Lipid Peroxidation and Ferroptosis. Redox Biology, 23, Article ID: 101107. [Google Scholar] [CrossRef] [PubMed]
[46] Fu, C., Wu, Y., Liu, S., Luo, C., Lu, Y., Liu, M., et al. (2022) Rehmannioside a Improves Cognitive Impairment and Alleviates Ferroptosis via Activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 Signaling Pathway after Ischemia. Journal of Ethnopharmacology, 289, Article ID: 115021. [Google Scholar] [CrossRef] [PubMed]

为你推荐