PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury

期刊论文
发表日期：

2024年1月29日

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Qianping Zhang,
Tiantian Sun,
Fan Yu,
Wei Liu,
Jin Gao,
Jinyu Chen,
Hao Zheng,
Jinming Liu,
Chenjian Miao,
Huanyi Guo,
Wu Tian,
Meihui Su,
Yingjie Guo,
Xi Liu,
Yandong Pei,
Zhuofei Wang,
Shang Chen,
Chenglong Mu,
Sin Man Lam,
Guanghou Shui,
Zongjin Li,
Zhongbo Yu,
Yan Zhang,
Guo Chen,
Congcong Lu,
Adam C. Midgley,
Changhua Li,
Xin Bian,
Xudong Liao,
Yong Wang,
Wei Xiong,
Hongying Zhu,
Yanjun Li,
Quan Chen

摘要

Synchronized ferroptosis contributes to nephron loss in acute kidneyinjury (AKI). However, the propagation signals and the underlying mechanisms of thesynchronized ferroptosis for renal tubular injury remain unresolved. Here we reportthat platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediatedsynchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLsin ferroptosis caused the instability of biomembranes and signaled the cell death ofneighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II)(PAFAH2) or by addition of antibodies against PAF. Genetic knockout orpharmacological inhibition of PAFAH2 increased PAF production, augmentedsynchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI.Notably, intravenous administration of wild-type PAFAH2 protein, but not itsenzymatically inactive mutants, prevented synchronized tubular cell death, nephronloss and AKI. Our findings offer an insight into the mechanisms of synchronizedferroptosis and suggest a possibility for the preventive intervention of AKI.