Zhang Qianping, Sun Tiantian, Yu Fan, Liu Wei, Gao Jin, Chen Jinyu, Zheng Hao, Liu Jinming, Miao Chenjian, Guo Huanyi, Tian Wu, Su Meihui, Guo Yingjie, Liu Xi, Pei Yandong, Wang Zhuofei, Chen Shang, Mu Chenglong, Lam Sin Man, Shui Guanghou, Li Zongjin, Yu Zhongbo, Zhang Yan, Chen Guo, Lu Congcong, Midgley Adam C, Li Changhua, Bian Xin, Liao Xudong, Wang Yong, Xiong Wei, Zhu Hongying, Li Yanjun, Chen Quan
Frontier Center for Cell Response, State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
College of Life Sciences, Zhejiang University, Hangzhou, China.
Nat Chem Biol. 2024 Jul;20(7):835-846. doi: 10.1038/s41589-023-01528-7. Epub 2024 Jan 29.
Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.
同步性铁死亡促成急性肾损伤（AKI）中的肾单位丢失。然而，肾小管损伤的同步性铁死亡的传播信号及潜在机制仍未明确。在此，我们报告血小板活化因子（PAF）和类PAF磷脂（PAF-LPLs）介导同步性铁死亡并导致AKI。PAF和PAF-LPLs在铁死亡中的出现导致生物膜不稳定，并向相邻细胞发出细胞死亡信号。这一级联反应可被PAF-乙酰水解酶（II）（PAFAH2）或添加抗PAF抗体所抑制。PAFAH2的基因敲除或药理学抑制会增加PAF生成，增强同步性铁死亡，并加剧缺血/再灌注（I/R）诱导的AKI。值得注意的是，静脉注射野生型PAFAH2蛋白，而非其酶活性失活的突变体，可预防肾小管细胞同步性死亡、肾单位丢失及AKI。我们的研究结果为同步性铁死亡的机制提供了见解，并提示了对AKI进行预防性干预的可能性。
