铁死亡在血管钙化疾病中的作用

doi:10.16352/j.issn.1001-6325.2026.03.0456

摘要/Abstract

摘要： 铁死亡作为一种铁依赖性细胞死亡方式,在血管钙化(VC)的发生与发展中扮演重要角色。其核心机制涉及细胞内铁超载、脂质过氧化物积累以及GPX4/GSH等抗氧化系统的失效。在慢性肾病、糖尿病和动脉粥样硬化等疾病背景下,铁死亡中SLC7A11-GPX4通路抑制、脂代谢紊乱以及铁自噬激活等过程,通过促进血管平滑肌细胞(VSMCs)的成骨样转分化、增强氧化应激与炎性反应,进而加速钙磷沉积和血管壁钙化。靶向铁死亡关键路径可显著减轻实验模型中的血管钙化程度,有望成为VC潜在的治疗靶点。

关键词: 血管钙化, 铁死亡, 慢性肾脏病

Abstract: Ferroptosis, as an iron-dependent form of cell death, plays a crucial role in the onset and progression of vascular calcification (VC). Its core mechanisms involve intracellular iron overload, accumulation of lipid per oxidation, and the failure of antioxidant systems represented by GPX4/GSH. In the context of chronic kidney disease, diabetes, and atherosclerosis, processes of ferroptosis, such as the inhibition of the SLC7A11-GPX4 pathway, lipid metabolism disorders, and ferritinophagy, promote the osteoblast-like trans-differentiation of vascular smooth muscle cells (VSMCs); enhance oxidative stress and inflammatory responses, thereby accelerating calcium and phosphate deposition and vascular calcification. Targeting ferroptosis pathways significantly reduces calcification in experimental models, suggesting potential therapeutic strategies for VC.

Key words: vascular calcification, ferroptosis, chronic kidney disease

中图分类号:

吴慧琳, 袁芳. 铁死亡在血管钙化疾病中的作用[J]. 基础医学与临床, 2026, 46(3): 456-461.

WU Huilin, YUAN Fang. Role of ferroptosis in vascular calcification diseases[J]. Basic & Clinical Medicine, 2026, 46(3): 456-461.

参考文献

[1] JW, Junling Z, Qiong T, et al. The significance of serum SLC7A11 levels in the occurrence of vascular calcification in maintenance peritoneal dialysis patients[J]. Nephrology(Carlton), 2024. doi:10.1111/nep.14334.
[2] 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: 1259-1275. doi:10.1016/j.kint.2022.07.034.
[3] Xu R, Huang Y, Zhu D, et al. Iron promotes Slc7a11-deficient valvular interstitial cell osteogenic differentia-tion: a possible mechanism by which ferroptosis partici-pates in intraleaflet hemorrhage-induced calcification[J]. Free Radic Bio Med, 2022, 184: 158-169. doi:10.1016/j.freeradbiomed.2022.03.013.
[4] Shao S, Liu Y, Hong W, et al. Influence of FOSL1 inhibition on vascular calcification and ROS generation through ferroptosis via P53-SLC7A11 axis[J]. Biomedicines, 2023, 11: 635. doi:10.3390/biomedicines11020635.
[5] He W, Meng Y, Liu W, et al. Protein kinase D knockdown alleviates vascular calcification through P53-SLC7A11 axis-mediated ferroptosis[J]. FASEB J, 2025, 39: e70706. doi:10.1096/fj.202402701RR.
[6] An Q, Sun H, Yang B, et al. Histone methyltransferase G9a drives ferroptosis to aggravate vascular calcification by inhibiting SLC7A11 transcription[J]. Cell Signal, 2025, 135: 112010. doi:10.1016/j.cellsig.2025.112010.
[7] Xiong L, Xiao Q, Chen R, et al. Histone deacetylase 9 promotes osteogenic trans-differentiation of vascular smooth muscle cells via ferroptosis in chronic kidney disease vascular calcification[J]. Ren Fail, 2024, 46: 2422435. doi:10.1080/0886022X.2024.2422435.
[8] Cai W, Liu L, Shi X, et al. Alox15/15-HpETE aggra-vates myocardial ischemia-reperfusion injury by promoting cardiomyocyte ferroptosis[J]. Circulation, 2023, 147: 1444-1460.
[9] 韩迎春,张继超, 张聪聪, 等.花生四烯酸Alox15/12-HETE代谢通路抑制血管钙化的发生[J]. 生理学报, 2021, 73: 571-576.
[10] Lu L, Ye Y, Chen Y, et al. Oxidized phospholipid POVPC contributes to vascular calcification by triggering ferroptosis of vascular smooth muscle cells[J]. FASEB J, 2024, 38. doi:10.1096/fj.202302570R.
[11] Ma WQ, Sun XJ, Zhu Y, et al. Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects[J]. Free Radic Biol Med, 2021, 165: 229-242. doi:10.1016/j.freeradbiomed.2021.01.033.
[12] Wu Y, Yang B, Sum H, et al. SREBP1 deficiency aggravates vascular calcification via iASPP-triggered ferroptosis of vascular smooth muscle cells[J]. Cardiovasc Diabetol, 2025, 24: 236. doi:10.1186/s12933-025-02797-3.
[13] Zhao L, Yang N, Song Y, et al. Effect of iron overload on endothelial cell calcification and its mechanism[J]. Ann Transl Med, 2021, 9: 1658. doi:10.21037/atm-21-5666.
[14] Aierken Y, He H, Li R, et al. Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells[J]. Cardiovasc Diabetol, 2024, 23: 186. doi:10.1186/s12933-024-02224-z.
[15] Becs G, Zarjou A, Agaral A, et al. Pharmacological induction of ferritin prevents osteoblastic transformation of smooth muscle cells[J]. J Cell Mol Med, 2016, 20: 217-230. doi:10.1111/jcmm.12682.
[16] Chen Z, Sun X, Li X, et al. Oleoylethanolamide alleviates hyperlipidaemia-mediated vascular calcification via attenuating mitochondrial DNA stress triggered autophagy-dependent ferroptosis by activating PPARα[J]. Biochem Pharmacol, 2023, 208: 115379. doi:10.1016/j.bcp.2022.115379.
[17] Sun DY, Wu WB, Wu JJ, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence[J]. Nat Commun, 2024, 15. doi:10.1038/s41467-024-45823-w.
[18] Wang Y, Zhang Y, Gao M, et al. Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy[J]. Cell Death Dis, 2024, 15: 865. doi:10.1038/s41419-024-07260-x.
[19] Hu Y, Gu X, Zhang Y, et al. Adrenomedullin, transcriptionally regulated by vitamin D receptors, alleviates atherosclerosis in mice through suppressing AMPK-mediated endothelial ferroptosis[J]. Environ Toxicol, 2024, 39: 199-211. doi:10.1002/tox.23958.
[20] Zou Y, Li D, Guan G, et al. Phosphoglycerate dehydrogenase overexpression inhibits ferroptosis to repress calcification of human coronary artery vascular smooth muscle cells via the P53/SLC7A11 pathway[J]. Int J Gen Med, 2024, 17: 3673-3687. doi:10.2147/IJGM.S473908.
[21] Zhang J, Wang X, Guan B, et al. Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway[J]. J Ethnopharmacol, 2023, 301. doi:10.1016/j.jep.2022.115852.
[22] 秦合伟,孙孟艳,王梦楠,等.黄芪甲苷Nrf2/HO-1/GPX4通路抑制铁死亡改善ApoE^-/-小鼠动脉粥样硬化的机制研究[J].中国中药杂志,2024,49:3619-3626.
[23] Feng Q, He L, He Y, et al. Fisetin ameliorates vascular calcification by regulating HNRNPA1-mediated ferroptosis[J]. Ann Vasc Surg, 2026, 122: 76-85. doi:10.1016/j.avsg.2025.05.056.
[24] Wang S, Gu J, Bian J, et al. Nesfatin-1 mitigates calcific aortic valve disease via suppressing ferroptosis mediated by GSH/GPX4 and ZIP8/SOD2 axes[J/OL]. Free Radic Biol Med, 2024, 222. doi:10.1016/j.freeradbiomed.2024.06.004.