Phenazine-1-Carboxylic Acid Inhibits Ferroptosis by Stabilizing EHMT2

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.