GPX4
GPX4 (glutathione peroxidase 4) is an enzyme that uses glutathione to disarm oxidised fats in cell membranes. It is the cell's main brake on ferroptosis, a form of cell death driven by fat oxidation.
Also called glutathione peroxidase 4, phospholipid hydroperoxide glutathione peroxidase.
GPX4 takes electrons from reduced glutathione to turn damaging lipid peroxides into harmless alcohols, producing oxidised glutathione as it goes. That ties it directly to the cell's glutathione supply.
In paired samples from 55 people with osteoarthritis, GPX4 was significantly lower in osteoarthritic cartilage than in undamaged cartilage (Miao 2022). Lowering GPX4 made cartilage cells more sensitive to oxidative stress and worsened matrix breakdown, and lowering it in an animal model worsened osteoarthritis (Miao 2022).
Two studies in mice tied cartilage protection to GPX4. NAC delivered in cartilage-targeted nanoparticles worked through GPX4, and its effect disappeared in mice lacking it (Wang 2026), while dihydrolipoic acid preserved glutathione and GPX4 in cartilage cells and in cartilage (Chen 2026).
Sources
- Miao Y, Chen Y, Xue F et al. Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression. EBioMedicine 2022.
- Wang S, Zhang F, Zhou X et al. Chondrocyte-Targeted Nanoparticles Loaded with N-Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance. Small Sci 2026.
- Chen Y, Fang J, Zhou Z et al. Dihydrolipoic acid suppresses ferroptosis in chondrocytes to ameliorate the progression of osteoarthritis by modulating the FOXO1/TXNIP signaling pathway. Free Radic Biol Med 2026.
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