Glutathione peroxidase 4 and other selenoproteins (GPX4)

Glutathione peroxidase 4 (GPX4) is a specialized antioxidant enzyme and a member of the selenoprotein family, uniquely capable of reducing complex lipid hydroperoxides within biological membranes (UniProt P36969). It utilizes a catalytic selenocysteine residue and glutathione as a reducing agent to maintain membrane integrity and prevent the accumulation of lethal lipid reactive oxygen species (Labunskyy et al., 2014). GPX4 is recognized as the master regulator of ferroptosis, an iron-dependent form of regulated cell death that is distinct from apoptosis and necrosis (Dixon et al., 2012). In many cancers, particularly those that have acquired resistance to conventional therapies or exist in a mesenchymal state, GPX4 becomes essential for survival, presenting a significant therapeutic vulnerability (Viswanathan et al., 2017). Beyond GPX4, the selenoprotein family includes 24 other members in humans, such as thioredoxin reductases and other glutathione peroxidases, which collectively manage cellular redox homeostasis and are often involved in similar pathological processes (Labunskyy et al., 2014). Small-molecule inhibitors like RSL3 and the FDA-approved drug altretamine target GPX4 to induce ferroptosis in susceptible cells, though the essential nature of GPX4 in healthy tissues like the brain and kidneys poses a challenge for clinical development (Yang et al., 2014).

Other names

Phospholipid hydroperoxide glutathione peroxidasePHGPxGPX4Selenoprotein familyGpx4

Covalent inhibition of the active site selenocysteine in GPX4, preventing the reduction of lipid hydroperoxides and triggering ferroptosis.