Covalent inhibition of ACSL4 alleviates ferroptosis-induced acute liver injury

Abstract

Ferroptosis, a form of regulated cell death, is characterized by iron-dependent phospholipid peroxidation and is closely linked to various liver diseases. Although covalent inhibitors have gained attention for their high potency and prolonged effects, no specific covalent inhibitor for ferroptosis exists. Here, we identify Rociletinib (ROC) as a potent inhibitor of ferroptosis through virtual screening and mechanistic studies. Our results demonstrate that ROC covalently binds to cysteine 170 of ACSL4, inhibiting its enzymatic activity and thereby suppressing lipid peroxidation and ferroptosis. ROC effectively mitigates ferroptosis-mediated acute liver injury in mouse models. These findings establish ROC as the targeted covalent inhibitor directly targeting ACSL4, offering a promising therapeutic strategy for ferroptosis-related diseases.