Insight the mechanism of ferroptosis inhibition by ferrostatin-1

Ferroptosis is a form of cell death primed by iron and lipid hydroperoxides and hence prevented by GPx4. Ferrostatin-1 (Fer-1) inhibits ferroptosis more efficiently than phenolic antioxidants. Previous studies on the reaction of Fer-1 adopted the kinetic test where a diazo-compound generates the hydroperoxyl radical to be reduced. However, this “chain breaking” effect is not satisfying for ferrous iron dependent peroxidation. New chain reactions, indeed, are primed from hydroperoxides produced by the antioxidant. On liposomes containing traces of lipid hydroperoxides and exposed to ferrous iron we disclosed by oxi-lipidomics the species produced and deduced the pattern of radical reactions. Although Fer-1 inhibits peroxidation, the pattern of oxidized species produced from pre-existing hydroperoxides was practically identical to that observed following exhaustive lipid peroxidation. This supported the notion that the anti-ferroptotic activity of Fer-1 descends from the scavenging of alkoxyl radicals generated by ferrous iron from lipid hydroperoxides. Thereof, Fer-1, in the presence if iron, eliminates lipid hydroperoxides and this produces the same anti-ferroptotic effect as GPx4, although generating a series of oxidized species but not just hydroxy fatty acids derivatives.