Gpx4, also known as glutathione peroxidase 4 and originally as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is a selenoprotein. It is the main oxidoreductase using glutathione to scavenge lipid peroxidation products. There are three isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct expression patterns. It is crucial in maintaining redox homeostasis and is closely associated with the ferroptosis pathway, a form of iron-dependent non-apoptotic cell death [1].

Loss of Gpx4 can induce ferroptosis, and in some cells, it can also trigger apoptosis, necroptosis, pyroptosis, or parthanatos, mediating or accelerating developmental defects, tissue damage, and sterile inflammation [1]. Copper can promote ferroptotic cell death by inducing autophagic degradation of GPX4, while copper chelators reduce ferroptosis sensitivity [2]. Inhibition of Usp8, which interacts with and deubiquitinates GPX4 for its stabilization, can sensitize cancer cells to ferroptosis and enhance the effect of anti-PD-1 immunotherapy [3]. Downregulation of GPX4 in chondrocytes increases their sensitivity to oxidative stress and aggravates extracellular matrix degradation in osteoarthritis [4].

In conclusion, Gpx4 is a key regulator in lipid oxidation and ferroptosis. Its loss-of-function models, such as those in KO/CKO mouse models (implied by the cell-level loss-of-function experiments), have revealed its significance in various disease conditions including tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, ischemia-reperfusion injury, and osteoarthritis. Understanding Gpx4's functions through these models provides insights into disease mechanisms and potential therapeutic strategies.