GPX4 (Phospholipid Hydroperoxide Glutathione Peroxidase)

GPX4 is a critical antioxidant enzyme that directly reduces phospholipid hydroperoxides within cellular membranes and lipoproteins, protecting cells from oxidative damage and ferroptosis—a non-apoptotic cell death driven by iron-dependent lipid reactive oxygen species accumulation (UniProt: P36969). The selenocysteine residue at its active site is essential for resistance to overoxidation and for preventing ferroptosis-mediated death in specific neuronal populations, including parvalbumin-positive interneurons. Beyond its antioxidant role, GPX4 supports male fertility, photoreceptor survival, and T-cell immune responses.

GPX4 is broadly expressed and participates in cellular redox homeostasis and lipid metabolism pathways. Clinically, biallelic GPX4 mutations cause Spondylometaphyseal Dysplasia, Sedaghatian type (SMDS), a severe neonatal lethal condition characterized by skeletal, cardiac, and neurological abnormalities (UniProt: P36969, MIM 250220).

In Alzheimer's Disease, GPX4 is significantly downregulated in post-mortem AD brain tissue relative to age-matched controls (mean log2 fold-change: −0.39; Chaparral AD proteomics). This reduction in a key ferroptosis-protective enzyme may contribute to neurodegeneration through increased lipid peroxidation and iron-dependent cell death pathways implicated in neuroinflammation and neuronal loss.