Formoterol, a clinically approved drug, inhibits ferroptosis by suppressing lipid peroxidation and attenuates APAP-induced acute liver injury

Abstract

Ferroptosis is an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation and implicated in various human diseases. Despite intensive research, clinically applicable ferroptosis inhibitors remain unavailable. In this study, we identify formoterol, a β₂-adrenergic agonist widely used to treat asthma and COPD, as a potent and selective ferroptosis inhibitor through scaffold-based screening of FDA-approved drugs. Formoterol confers robust protection against ferroptotic cell death induced by diverse triggers across multiple human and rodent cell lines, functioning independently of classical pathways such as GPX4, FSP1, or iron chelation. Mechanistic studies reveal that formoterol suppresses ferroptosis by directly scavenging lipid peroxyl radicals, mediated by its unique ortho-amino phenol moiety. In vivo, formoterol significantly alleviates acetaminophen-induced acute liver injury, reducing hepatic lipid peroxidation and preserving tissue integrity. These findings establish formoterol as a clinically approved agent with previously unrecognized anti-ferroptotic activity, offering a compelling example of drug repurposing to accelerate the development of ferroptosis-targeted therapies.