Ferroptosis as a distinct form of programmed cell death was first described through a screen for anticancer drugs that identified erastin, a chemical that inhibits the Xc− system. Xc− system is the glutamate/cysteine antiporter in the plasma membrane through which cystine is imported into the cell. Within the cell, cystine is converted to cysteine, which is used to synthesize glutathione. Glutathione serves as a substrate for glutathione peroxidase (GPX4), which protects cells against oxidative stress by converting hydrogen peroxide to water. Additionally, GPX4 coverts toxic lipid peroxides to nontoxic lipid alcohols. Thus erastin induces lipid peroxidation and consequently ferroptosis through its inhibition of the Xc− system, which indirectly reduces GPX4 activity.
