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.

同步性铁死亡会导致急性肾损伤 (AKI) 中的肾单位损失。然而，肾小管损伤同步铁死亡的传播信号和潜在机制仍未解决。在此，我们报道血小板激活因子 (PAF) 和 PAF 样磷脂 (PAF-LPL) 介导同步铁死亡并导致 AKI。铁死亡中 PAF 和 PAF-LPL 的出现导致生物膜不稳定，并发出邻近细胞死亡的信号。PAF-乙酰水解酶 (II) (PAFAH2) 或添加抗 PAF 抗体可抑制该级联反应。PAFAH2 的基因敲除或药物抑制会增加 PAF 的产生，增强同步铁死亡并加剧缺血/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（而非其酶促无活性突变体）可防止同步肾小管细胞死亡、肾单位丢失和 AKI。我们的研究结果提供了对同步性铁死亡机制的深入了解，并提出了 AKI 预防性干预的可能性。