心血管疾病的铁死亡机制

doi:10.3969/j.issn.1003-9198.2025.09.020

摘要/Abstract

摘要： 铁死亡在过去10年中已成为研究热点,其与自噬、坏死等不同,具有铁累积和脂毒性的代谢特征。研究表明,谷胱甘肽过氧化物酶4(GPX4)作为铁死亡的关键蛋白,参与了心肌炎等多种心血管疾病的发展。然而,铁死亡在各种心血管疾病中的作用尚不清楚。本文介绍了铁死亡的机制,并探讨了铁死亡在心脏微环境各种细胞中的作用及其对众多心血管疾病的意义。最后,本文提出,针对铁死亡相关病理机制的靶向治疗可能为相关疾病的临床治疗提供新希望。

关键词: 铁死亡, 心血管疾病, 脂质过氧化, 铁代谢

Abstract: Ferroptosis has become a research hotspot over the last 10 years. Unlike autophagy or necrosis, it is characterized by iron accumulation and lipotoxicity. It has been found that glutathione peroxidase 4 (GPX4), as a key protein of ferroptosis, is involved in the development of various cardiovascular diseases such as myocarditis. However, the mechanism of ferroptosis in various cardiovascular diseases remains unclear. In this article, we present the mechanisms of ferroptosis and its effects on various cells within the cardiac microenvironment, and investigate its significance in diverse cardiovascular diseases. Finally, we propose that targeting ferroptosis-related pathomechanisms may offer new hope for the treatment of related diseases.

Key words: ferroptosis, cardiovascular disease, lipid peroxidation, iron metabolism

中图分类号:

R 54

陈亚鹏, 胡佳伟, 孔祥权, 张俊杰. 心血管疾病的铁死亡机制[J]. 实用老年医学, 2025, 39(9): 957-962.

CHEN Yapeng, HU Jiawei, KONG Xiangquan, ZHANG Junjie. Mechanisms of ferroptosis in cardiovascular diseases[J]. Practical Geriatrics, 2025, 39(9): 957-962.

参考文献

[1] ROTH G A, MENSAH G A, JOHNSON C O, et al. Globalburden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study[J]. J Am Coll Cardiol, 2020, 76(25): 2982-3021.
[2] XU W, LEE A L, LAM C L K, et al. Benefits and risks associated with statin therapy for primary prevention in old and very old adults: real-world evidence from a target trial emulation study[J]. Ann Intern Med, 2024, 177(6): 701-710.
[3] ABDELLATIF M, SCHMID S T, FUERLINGER A, et al. Anti-ageing interventions for the treatment of cardiovascular disease[J]. Cardiovasc Res, 2024: cvae177.
[4] DEL RE D P, AMGALAN D, LINKERMANN A, et al. Fundamental mechanisms of regulated cell death and implications for heart disease[J]. Physiol Rev, 2019, 99(4): 1765-1817.
[5] ZHENG J, CONRAD M. Ferroptosis: when metabolism meets cell death[J]. Physiol Rev, 2025, 105(2): 651-706.
[6] DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072.
[7] QIN Y, QIAO Y, WANG D, et al. Ferritinophagy and ferroptosis in cardiovascular disease:mechanisms and potential applications[J]. Biomed Pharmacother, 2021, 141: 111872.
[8] HOU W, XIE Y, SONG X, et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425-1428.
[9] KERINS M J, OOI A. The roles of NRF2 in modulating cellular iron homeostasis[J]. Antioxid Redox Signal, 2018, 29(17): 1756-1773.
[10] ANANDHAN A, DODSON M, SHAKYA A, et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8[J]. Sci Adv, 2023, 9(5): eade9585.
[11] ZHAO Z. Hydroxyl radical generations form the physiologically relevant Fenton-like reactions[J]. Free Radic Biol Med, 2023, 208: 510-515.
[12] KAGAN V E, MAO G, QU F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nat Chem Biol, 2017, 13(1): 81-90.
[13] KOPPULA P, ZHUANG L, GAN B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620.
[14] LEWERENZ J, HEWETT S J, HUANG Y, et al. The cystine/glutamate antiporter system x(c) (-) in health and disease: from molecular mechanisms to novel therapeutic opportunities[J]. Antioxid Redox Signal, 2013, 18(5): 522-555.
[15] KOPPULA P, ZHANG Y, ZHUANG L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun:Lond, 2018, 38(1): 12.
[16] TRIMM E, RED-HORSE K. Vascular endothelial cell development and diversity[J]. Nat Rev Cardiol, 2023, 20(3): 197-210.
[17] XU S, ILYAS I, LITTLE P J, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies[J]. Pharmacol Rev, 2021, 73(3): 924-967.
[18] BAI T, LI M, LIU Y, et al. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell[J]. Free Radic Biol Med, 2020, 160: 92-102.
[19] MA H, HUANG Y, TIAN W, et al. Endothelial transferrin receptor 1 contributes to thrombogenesis through cascade ferroptosis[J]. Redox Biol, 2024, 70: 103041.
[20] QIN X, ZHANG J, WANG B, et al. Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells[J]. Autophagy, 2021, 17(12): 4266-4285.
[21] MIANO J M, FISHER E A, MAJESKY M W. Fate and state of vascular smooth muscle cells in atherosclerosis[J]. Circulation, 2021, 143(21): 2110-2116.
[22] YE Y, CHEN A, LI L, et al. Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification[J]. Kidney Int, 2022, 102(6): 1259-1275.
[23] ZHANG F, LI K, ZHANG W, et al. Ganglioside GM3 protects against abdominal aortic aneurysm by suppressing ferroptosis[J]. Circulation, 2024, 149(11): 843-859.
[24] SUN D Y, WU W B, WU J J, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence[J]. Nat Commun, 2024, 15(1): 1429.
[25] FANG X, ARDEHALI H, MIN J, et al. The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease[J]. Nat Rev Cardiol, 2023, 20(1): 7-23.
[26] WANG X, CHEN X, ZHOU W, et al. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways[J]. Acta Pharm Sin B, 2022, 12(2): 708-722.
[27] WANG B, JIN Y, LIU J, et al. EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2[J]. Redox Biol, 2023, 65: 102825.
[28] CAI W, LIU L, SHI X, et al. Alox15/15-HpETE aggravates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis[J]. Circulation, 2023, 147(19): 1444-1460.
[29] KONG P, CUI Z Y, HUANG X F, et al. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention[J]. Signal Transduct Target Ther, 2022, 7(1): 131.
[30] DAMLUJI A A, VAN DIEPEN S, KATZ J N, et al. Mechanical complications of acute myocardial infarction: a scientific statement from the American Heart Association[J]. Circulation, 2021, 144(2): e16-e35.
[31] PARK T J, PARK J H, LEE G S, et al. Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes[J]. Cell Death Dis, 2019, 10(11): 835.
[32] YU Q, ZHANG N, GAN X, et al. EGCG attenuated acute myocardial infarction by inhibiting ferroptosis via miR-450b-5p/ACSL4 axis[J]. Phytomedicine, 2023, 119: 154999.
[33] MIAO M, CAO S, TIAN Y, et al. Potential diagnostic biomarkers: 6 cuproptosis- and ferroptosis-related genes linking immune infiltration in acute myocardial infarction[J]. Genes Immun, 2023, 24(4): 159-170.
[34] XIANG Q, YI X, ZHU X H, et al. Regulated cell death in myocardial ischemia-reperfusion injury[J]. Trends Endocrinol Metab, 2024, 35(3): 219-234.
[35] TANG L J, LUO X J, TU H, et al. Ferroptosis occurs in phase of reperfusion but not ischemia in rat heart following ischemia or ischemia/reperfusion[J]. Naunyn Schmiedebergs Arch Pharmacol, 2021, 394(2): 401-410.
[36] DODSON M, CASTRO-PORTUGUEZ R, ZHANG D D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis[J]. Redox Biol, 2019, 23: 101107.
[37] XU S, WU B, ZHONG B, et al. Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/System xc-/glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis[J]. Bioengineered, 2021, 12(2): 10924-10934.
[38] MOE G W, MARÍN-GARCÍA J. Role of cell death in the progression of heart failure[J]. Heart Fail Rev, 2016, 21(2): 157-167.
[39] HAN Q, SHI J, YU Y, et al. Calycosin alleviates ferroptosis and attenuates doxorubicin-induced myocardial injury via the Nrf2/SLC7A11/GPX4 signaling pathway[J]. Front Pharmacol, 2024, 15: 1497733.
[40] LI N, JIANG W, WANG W, et al. Ferroptosis and its emerging roles in cardiovascular diseases[J]. Pharmacol Res, 2021, 166: 105466.
[41] RUAN Y, ZHANG L, ZHANG L, et al. Therapeutic approaches targeting ferroptosis in cardiomyopathy[J]. Cardiovasc Drugs Ther, 2025, 36(3):595-613.
[42] TANG Z, HUANG X, MEI H, et al. Silencing of METTL3 suppressed ferroptosis of myocardial cells by m6A modification of SLC7A11 in a YTHDF2 manner[J]. J Bioenerg Biomembr, 2024, 56(2): 149-157.
[43] GU J J, DU T J, ZHANG L N, et al. Identification of ferroptosis-related genes in heart failure induced by transverse aortic constriction[J]. J Inflamm Res, 2023, 16: 4899-4912.
[44] WANG M, MO D, ZHANG N, et al. Ferroptosis in diabetic cardiomyopathy: advances in cardiac fibroblast-cardiomyocyte interactions[J]. Heliyon, 2024, 10(15): e35219.
[45] SONG Z, WANG J, ZHANG L. Ferroptosis: a new mechanism in diabetic cardiomyopathy[J]. Int J Med Sci, 2024, 21(4): 612-622.
[46] ZHUANG S, MA Y, ZENG Y, et al. METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis[J]. Cell Biol Toxicol, 2023, 39(3): 1015-1035.