Dietary Induction and Modulation of Ferroptosis in Caenorhabditis elegans

SUMMARY Ferroptosis is an iron-dependent form of regulated cell death associated with oxidized polyunsaturated phospholipids. Understanding the role of this process in vivo has been slowed by the lack of readily accessible model systems. Exposing the nematode Caenorhabditis elegans to the polyunsaturated fatty acid dihomogamma-linolenic acid (DGLA; 20:3n-6) causes germ cell death and sterility that is largely independent of the canonical apoptosis pathway. Here we demonstrate that DGLA-induced germ cell death is modulated by small molecule ferroptosis inhibitors, genetic manipulation of ferritin, NADPH oxidase, and glutathione peroxidases, and by dietary co-supplementation with oleic acid. Thus, DGLA-induced germ cell death in C. elegans is highly analogous to ferroptosis in mammalian cells. DGLA can also induce ferroptosis in human cells, further highlighting this omega-6 PUFA as a metabolic instigator of ferroptosis. Together, these results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats. Highlights - Dietary dihomogamma-linolenic acid (DGLA)-induced germ cell death in C. elegans is alleviated by small molecule antioxidants and iron chelators - Dietary and endogenous oleic acid protects from DGLA-induced ferroptosis - Ether-lipid deficiency increases sensitivity to DGLA-induced ferroptosis - DGLA specifically induces ferroptosis in human cancer cells