Regulation of Ferroptosis Through the Cysteine-Glutathione Redox Axis

Abstract

Iron-mediated lipid peroxidation has a primary role in ferroptosis. Among a variety of antioxidative systems, glutathione peroxidase 4 (GPX4) is a potent protective enzyme against ferroptosis. Suppling reducing equivalents to GPX4 has been found to be important in terms of the function of glutathione from the standpoint of cell survival against ferroptosis. A cysteine deficiency results in elevated levels of free iron via ferritinophagy, resulting in a decrease in GPX4 activity caused by a decrease in glutathione production. Ferritinophagy releases redox-inactive ferric iron, which is then converted to redox-active ferrous iron by accepting an electron from radical compounds and results in lipid peroxidation. In many cases the availability of cysteine can hold the key to determining cell fate in vivo. The electron used in the lipid peroxidation reaction appears to be from the mitochondrial electron transport system under conditions of a cysteine deficiency but can also be obtained from other sources, depending on the circumstances.