唐志伟,刘浩宇

急性肾损伤（acute kidney injury，AKI）并非单一血流动力学事件，而是由缺血/再灌注、败血症、药物毒性与围术期应激等共同驱动的高度异质性综合征。传统研究多将肾小管损伤解释为凋亡或“意外坏死”，但近十余年的工作表明，铁死亡、焦亡、铜死亡、双硫死亡以及PANoptosis等新型调节性细胞死亡共同塑造了AKI的真实病理图景。本文以18篇代表性文献为核心，按照“死亡模块—串扰枢纽—修复转归—靶向策略”的逻辑，对AKI中的多重细胞死亡网络进行重构。现有证据提示：铁死亡是近端肾小管代谢崩溃的中心事件，焦亡负责将局部细胞损伤外溢为坏死性炎症，铜死亡和双硫死亡则揭示了金属稳态与细胞骨架应激的新边界；ROS、线粒体损伤、Caspase-8/TAK1与PANoptosome构成死亡程序切换的关键节点。更重要的是，急性期细胞死亡并不随肌酐下降而终止，而是通过失败修复小管、免疫细胞驻留与间质纤维化程序，推动AKI向CKD持续演进。基于此，未来治疗不应停留于单一通路拦截，而应转向分层识别、联合阻断以及红氧和代谢网络的整体重建。

急性肾损伤；调节性细胞死亡；铁死亡；焦亡；PANoptosis；AKI-CKD转化

[1] Ronco C,Bellomo R,Kellum JA.Acute kidney injury.Lancet,2019,394(10212):1949-1964. [2] Takeuchi T,Flannery AH,Liu LJ,et al.Epidemiology of sepsis-associated acute kidney injury in the ICU with contemporary consensus definitions.Critical Care,2025,29:128. [3] Dixon SJ,Lemberg KM,Lamprecht MR,et al.Ferroptosis:an iron-dependent form of nonapoptotic cell death.Cell,2012,149(5):1060-1072. [4] Friedmann Angeli JP,Schneider M,Proneth B,et al.Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.Nature Cell Biology,2014,16(12):1180-1191. [5] Deng F,Sharma I,Dai Y,et al.Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule.Journal of Clinical Investigation,2019,129(11):5033-5049. [6] Shi J,Zhao Y,Wang K,et al.Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.Nature,2015,526(7575):660-665. [7] Ye Z,Zhang L,Li R,et al.Caspase-11 mediates pyroptosis of tubular epithelial cells and septic acute kidney injury.Kidney and Blood Pressure Research,2019,44(4):465-478. [8] Xia W,Li Y,Wu M,et al.Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation.Cell Death&Disease,2021,12(2):139. [9] Tsvetkov P,Coy S,Petrova B,et al.Copper induces cell death by targeting lipoylated TCA cycle proteins.Science,2022,375(6586):1254-1261. [10] Chen S,Chen T,Xu C,et al.Iron overload exaggerates renal ischemia-reperfusion injury by promoting tubular cuproptosis via interrupting function of LIAS.Redox Biology,2025,86:103795. [11] Liu X,Nie L,Zhang Y,et al.Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis.Nature Cell Biology,2023,25(3):404-414. [12] Bedoui S,Herold MJ,Strasser A.Emerging connectivity of programmed cell death pathways and its physiological implications.Nature Reviews Molecular Cell Biology,2020,21(11):671-684. [13] Wang Y,Kanneganti TD.From pyroptosis,apoptosis and necroptosis to PANoptosis:A mechanistic compendium of programmed cell death pathways.Computational and Structural Biotechnology Journal,2021,19:4641-4657. [14] Dodson M,Castro-Portuguez R,Zhang DD.NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis.Redox Biology, 2019,23:101107. [15] Müller T,Dewitz C,Schmitz J,et al.Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure.Cellular and Molecular Life Sciences,2017,74(19):3631-3645. [16] Venkatachalam MA,Weinberg JM,Kriz W,et al.Failed tubule recovery,AKI-CKD transition,and kidney disease progression.Journal of the American Society of Nephrology,2015,26(8):1765-1776. [17] Kirita Y,Wu H,Uchimura K,et al.Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury.Proceedings of the National Academy of Sciences of the United States of America,2020,117(27):15874-15883. [18] Kuppe C,Ibrahim MM,Kranz J,et al.Decoding myofibroblast origins in human kidney fibrosis.Nature,2021,589(7841):281-286.

点击下载PDF