GPX4-AUTAC

GPX4-AUTAC is a novel small molecule designed as an AUTAC (autophagy-targeting chimera) that selectively induces the autophagic degradation of glutathione peroxidase 4 (GPX4), a key enzyme protecting cells from lipid peroxidation and ferroptosis. By promoting the ubiquitination of GPX4 via TRAF6 and enhancing its recognition by p62, GPX4-AUTAC triggers selective autophagy-dependent degradation of GPX4. This leads to robust induction of ferroptosis—a form of regulated cell death driven by iron-dependent lipid peroxidation—in cancer cells, particularly breast cancer models. Preclinical studies demonstrate potent anti-cancer activity in vitro, in vivo, and in patient-derived organoids. Combination with other ferroptosis inducers or chemotherapy shows synergistic effects against breast cancer[1]. The drug represents a targeted protein degradation strategy for cancers dependent on GPX4-mediated survival.