Ferroptosis

Ferroptosis is a form of regulated cell death that is iron-dependent and driven by the accumulation of lipid hydroperoxides in cellular membranes. It is morphologically and biochemically distinct from other forms of cell death such as apoptosis, necroptosis, and pyroptosis, and has been studied as a potential contributor to various diseases and therapies.

The core mechanism involves iron-catalyzed lipid peroxidation and the failure of antioxidant defenses that normally restrict this process. Cells import cystine via the system Xc- antiporter, which supports glutathione synthesis. Glutathione, in turn, serves as a substrate for the enzyme GPX4, which reduces lipid hydroperoxides and prevents membrane damage. Inhibition of system Xc- (for example by erastin) or direct inhibition of GPX4 (for example by RSL3) impairs this detoxification, allowing lipid peroxides to accumulate and trigger ferroptotic cell death. Iron availability and trafficking enhance this lipid peroxidation process, while iron chelators can suppress ferroptosis. Other players include ACSL4, which promotes incorporation of polyunsaturated fatty acids into membrane phospholipids, making them susceptible to peroxidation, and lipoxygenases that contribute to lipid oxidation.

Ferroptosis has been implicated in cancer, where inducing ferroptosis may overcome resistance to other therapies, as well as in neurodegenerative and ischemic diseases where unwanted cell loss occurs. Pharmacological compounds such as ferrostatin-1 and liproxstatin-1 can inhibit ferroptosis, whereas erastin and RSL3 can promote it, providing tools for research and potential therapeutic avenues. Biomarkers include lipid peroxidation products, depleted glutathione, and changes in GPX4 activity.