Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals
Uladzimir Barayeu, Danny Schilling, Mohammad Eid, Thamara Nishida Xavier da Silva, Lisa Schlicker, Nikolina Mitreska, Christopher Zapp, Frauke Gräter, Aubry K. Miller, Reinhard Kappl, Almut Schulze, José Pedro Friedmann Angeli, Tobias P. Dick
Abstract
Abstract Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S 0 ) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for S 0 biosynthesis, cysteine can support ferroptosis resistance independently of the canonical GPX4 pathway. Our results further suggest that hydropersulfides terminate radical chain reactions through the formation and self-recombination of perthiyl radicals. The autocatalytic regeneration of hydropersulfides may explain why low micromolar concentrations of persulfides suffice to produce potent cytoprotective effects on a background of millimolar concentrations of glutathione. We propose that increased S 0 biosynthesis is an adaptive cellular response to radical-driven lipid peroxidation, potentially representing a primordial radical protection system.