PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury
By
Zhang, QP (Zhang, Qianping) [1] ; Sun, TT (Sun, Tiantian) [1] ; Yu, F (Yu, Fan) [1] ; Liu, W (Liu, Wei) [1] ; Gao, J (Gao, Jin) [1] ; Chen, JY (Chen, Jinyu) [2] ; Zheng, H (Zheng, Hao) [1] ; Liu, JM (Liu, Jinming) [1] ; Miao, CJ (Miao, Chenjian) [3] ; Guo, HY (Guo, Huanyi) [3] ; Tian, W (Tian, Wu) [4] ; Su, MH (Su, Meihui) [5] ; Guo, YJ (Guo, Yingjie) [6] ; Liu, X (Liu, Xi) [1] ; Pei, YD (Pei, Yandong) [1] ; Wang, ZF (Wang, Zhuofei) [7] ; Chen, S (Chen, Shang) [8] ; Mu, CL (Mu, Chenglong) [1] ; Lam, SM (Lam, Sin Man) [9] , [10] ; Shui, GH (Shui, Guanghou) [9] , [11] ; Li, ZJ (Li, Zongjin) [8] ; Yu, ZB (Yu, Zhongbo) [7] ; Zhang, Y (Zhang, Yan) [4] ; Chen, G (Chen, Guo) [1] ; Lu, CC (Lu, Congcong) [1] ; Midgley, AC (Midgley, Adam C.) [12] ; Li, CH (Li, Changhua) [5] ; Bian, X (Bian, Xin) [1] ; Liao, XD (Liao, Xudong) [1] ; Wang, Y (Wang, Yong) [2] ; Xiong, W (Xiong, Wei) [13] ; Zhu, HY (Zhu, Hongying) [13] ; Li, YJ (Li, Yanjun) [1] ; Chen, Q (Chen, Quan) [1]
(provided by Clarivate)
Early Access
JAN 2024
Indexed
2024-02-06
Document Type
Article; Early Access
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Abstract
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.
Platelet-activating factor (PAF) and PAF-like phospholipids were identified as propagators of ferroptosis, whereas PAFAH2 suppressed synchronized ferroptosis and, thus, prevented tubular cell death in acute kidney injury.
