Ferroptosis, a form of iron-dependent, lipid peroxidation-driven regulatory cell death, is implicated in multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, specific inhibitors of ferroptosis are not yet available. This study identifies AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. AS effectively inhibits lipid peroxidation and ferroptosis in human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4, inhibiting its enzymatic activity and suppressing lipid peroxidation and ferroptosis. Using nanoparticle-based delivery systems, AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). These findings identify AS as a specific and targeted inhibitor of ACSL4 with significant antiferroptosis function, providing a potential therapeutic approach for ferroptosis-related diseases.Ferroptosis, a form of iron-dependent, lipid peroxidation-driven regulatory cell death, is implicated in multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, specific inhibitors of ferroptosis are not yet available. This study identifies AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. AS effectively inhibits lipid peroxidation and ferroptosis in human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4, inhibiting its enzymatic activity and suppressing lipid peroxidation and ferroptosis. Using nanoparticle-based delivery systems, AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). These findings identify AS as a specific and targeted inhibitor of ACSL4 with significant antiferroptosis function, providing a potential therapeutic approach for ferroptosis-related diseases.