Melanin precursors mediated adaption to temperature changes in fungus and animal via inhibition of lipid-mediated ferroptosis.

The discovery of biological activities of natural products plays a vital part in drug development. The mechanism by which organisms respond to temperature changes via biosynthesis of natural products remained largely cryptic. A thermophilic fungus under cold stress turned black and accumulated a polyketide metabolite 1 and lipid mass. Deficiency in 1 caused melanin loss and accumulated extra lipid mass, unexpectedly leading to seriously damaged mitochondria diagnostic for ferroptosis. Further analysis revealed that lipid mass induced by cold stress intensively increased ferroptosis risk and 1 functioned as cell wall reinforcer against mass lipid accumulation and as reactive oxygen species scavenger against lipid peroxidation. We also found that melanin in mice lowered lipid level but enhanced animal resistance to cold stress. Treatment with melanin precursors significantly increased mouse cell survival rate under cold stress. Our results unveiled a metabolite-lipid-ferroptosis-cold relationship, which provided mechanistic insights into the functions of most common metabolites and into diseases related to cold stress. These findings opened a perspective for developing anti-cold and anti-ferroptosis therapeutics and agents.