Ferroptosis is a form of iron-dependent, lipid peroxidation-driven cell death involved in various diseases, including organ injury, ischemia/reperfusion, and neurodegenerative disorders. This study identifies AS-252424 (AS) as a potent and specific inhibitor of ferroptosis by directly binding to glutamine 464 of ACSL4, thereby suppressing lipid peroxidation and ferroptosis. AS effectively inhibits ferroptosis in both human and mouse cells, and treatment with AS-loaded nanoparticles alleviates ferroptosis-mediated organ injury in models of kidney ischemia/reperfusion and acute liver injury. Mechanistically, AS inhibits ACSL4 enzymatic activity, reducing lipid peroxidation and ferroptosis. AS is a selective PI3Kγ inhibitor, but its antiferroptotic effect is independent of PI3Kγ. AS directly binds to Q464 of ACSL4, inhibiting its activity and preventing ferroptosis. AS-NPs enhance drug delivery and efficacy in vitro and in vivo, protecting against I/R-induced acute kidney injury and ConA-induced acute lung injury. These findings highlight AS as a promising therapeutic agent for ferroptosis-related diseases.Ferroptosis is a form of iron-dependent, lipid peroxidation-driven cell death involved in various diseases, including organ injury, ischemia/reperfusion, and neurodegenerative disorders. This study identifies AS-252424 (AS) as a potent and specific inhibitor of ferroptosis by directly binding to glutamine 464 of ACSL4, thereby suppressing lipid peroxidation and ferroptosis. AS effectively inhibits ferroptosis in both human and mouse cells, and treatment with AS-loaded nanoparticles alleviates ferroptosis-mediated organ injury in models of kidney ischemia/reperfusion and acute liver injury. Mechanistically, AS inhibits ACSL4 enzymatic activity, reducing lipid peroxidation and ferroptosis. AS is a selective PI3Kγ inhibitor, but its antiferroptotic effect is independent of PI3Kγ. AS directly binds to Q464 of ACSL4, inhibiting its activity and preventing ferroptosis. AS-NPs enhance drug delivery and efficacy in vitro and in vivo, protecting against I/R-induced acute kidney injury and ConA-induced acute lung injury. These findings highlight AS as a promising therapeutic agent for ferroptosis-related diseases.