GPx4, lipid per oxidation, and cell death: discoveries, rediscoveries, and open issues

Iron-dependent lipid peroxidation is a complex oxidative process where phospholipid hydroperoxides (PLOOH) are produced in membranes and finally transformed into a series of decomposition products, some of which endowed with biological activity. It is specifically prevented by GPx4, the selenoenzyme that reduces PLOOH by glutathione (GSH). PLOOH is both a product and the major initiator of peroxidative chain reactions, as well as an activator of lipoxygenases. -Tocopherol both specifically breaks peroxidative chain propagation and inhibits lipoxygenases. Thus, GPx4, GSH and -tocopherol are integrated in a concerted anti-peroxidant mechanism. Recent Advances: Ferroptosis has been recently identified as a cell death subroutine specifically activated by missing GPx4 activity and inhibited by iron chelation or -tocopherol supplementation. Ferroptosis induction may underlie spontaneous human diseases, such as major neurodegeneration and neuroinflammation , causing an excessive cell death. The basic mechanism of ferroptosis, therefore, fits the features of activation of lipid peroxidation.