Phenazine‐1‐Carboxylic Acid Inhibits Ferroptosis by Stabilizing
EHMT2
Xue Sun, Yang Chen, Chaoyi Xia, Chong Wei, Junyi Shao, Dingyao Wang, Zixuan Fan, Jingshu Min, Caiyun Fu, Xi Wang ABSTRACT
Ferroptosis is a regulated form of cell death driven by iron‐dependent lipid peroxidation and implicated in the pathogenesis of various diseases. Identifying ferroptosis inhibitors may therefore provide therapeutic opportunities for these disorders. Here, we identified phenazine‐1‐carboxylic acid (PCA) as a potent ferroptosis inhibitor through high‐throughput screening. Mechanistically, PCA reduced the accumulation of intracellular reactive oxygen species (ROS) and lipid ROS in part by stabilizing the protein level of euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2). PCA also markedly alleviated cisplatin‐induced acute kidney injury (AKI) in mice. These findings identify a previously unrecognized ferroptosis‐suppressive function of PCA and support its further evaluation as a lead compound for ferroptosis‐associated diseases.