GPX4 (glutathione peroxidase 4) is an essential selenoprotein that serves as the primary cellular defense against ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation accumulation 1. The protein functions as an antioxidant enzyme that directly reduces phospholipid hydroperoxides, cholesterol hydroperoxides, and other lipid-based reactive oxygen species, thereby preventing membrane lipid peroxidation 2. GPX4 exists in three isoforms (cytosolic, mitochondrial, and nuclear) with distinct expression patterns and is regulated by post-translational modifications, particularly S-palmitoylation at specific cysteine residues, which affects protein stability and ferroptosis sensitivity 34. Beyond ferroptosis regulation, GPX4 deficiency can trigger multiple cell death pathways including apoptosis, necroptosis, and pyroptosis, and interacts with autophagy pathways to modulate cellular fate under oxidative stress 5. Clinically, GPX4 dysfunction is implicated in diverse pathological conditions including cancer, neurodegeneration, cardiovascular diseases, and ischemia-reperfusion injury 6. The R152H mutation in GPX4 causes Sedaghatian-type spondylometaphyseal dysplasia, a fatal skeletal disorder 5. Therapeutically, targeting GPX4 through ferroptosis induction represents a promising cancer treatment strategy, with several compounds showing efficacy by modulating GPX4 stability or enzymatic activity 78.