GPX4 Gene: Function, Mutations, and Disease Associations | Ferroptosis Regulator

The GPX4 gene encodes glutathione peroxidase 4, a selenium-dependent phospholipid hydroperoxidase that reduces lipid hydroperoxides to their corresponding alcohols, protecting cells against oxidative membrane damage. It is a critical inhibitor of ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. GPX4 is expressed as multiple isoforms (mitochondrial, cytosolic, and nuclear) with distinct subcellular localizations and functions. Beyond its antioxidant role, GPX4 is involved in spermatogenesis, embryonic development, and immune regulation. Mutations in GPX4 are associated with spondylometaphyseal dysplasia (SMD) and Sedaghatian-type, while dysregulated expression is linked to various cancers and neurodegenerative diseases.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Ferroptosis (hsa04216)

• Glutathione metabolism (hsa00480)

• Metabolism of lipids (Reactome: R-HSA-556833)

• Selenium micronutrient network (Reactome: R-HSA-2408557)

• Oxidative stress response (Reactome: R-HSA-2262752)

GPX4 is a 197-amino acid selenoprotein (UniProt P36969) that exists in three isoforms: mitochondrial (mtPHGPx), cytosolic (cPHGPx), and nuclear (snPHGPx). The protein contains a selenocysteine residue at position 73, which is essential for its catalytic activity. GPX4 reduces phospholipid hydroperoxides, cholesterol hydroperoxides, and thymine hydroperoxides, using glutathione as a cofactor. It is a key regulator of ferroptosis, preventing lipid peroxidation-induced cell death. Structurally, GPX4 is a monomeric enzyme with a thioredoxin-like fold. Its expression is regulated by Nrf2 and selenium availability. Post-translational modifications include phosphorylation and ubiquitination, affecting stability and activity. GPX4 also plays a role in sperm maturation and male fertility.