Ferroptosis inhibition by oleic acid mitigates iron-overload-induced injury

Iron overload, characterized by accumulation of iron in tissues, induces a multiorgan toxicity whose mechanisms are not fully understood. Using cultured cell lines, Caenorhabditis elegans, and mice, we found that ferroptosis occurs in the context of iron-overload-mediated damage. Exogenous oleic acid protected against iron-overload-toxicity in cell culture and Caenorhabditis elegans by suppressing ferroptosis. In mice, oleic acid protected against FAC-induced liver lipid peroxidation and damage. Oleic acid changed the cellular lipid composition, characterized by decreased levels of polyunsaturated fatty acyl phospholipids and decreased levels of ether-linked phospholipids. The protective effect of oleic acid in cells was attenuated by GW6471 (a PPAR-?? antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR-?? functional homologue). These results highlight ferroptosis as a driver of iron-overload-mediated damage, which is inhibited by oleic acid. This monounsaturated fatty acid represents a potential therapeutic approach to mitigating organ damage in iron overload individuals. Overall design: To investigate the effect of oleic acid supplementation on ferric ammonium citrate (FAC induced) ferroptosis, we cultured HEK293 cells under 4 conditions: vehicle, oleic acid supplemented, FAC (ferroptosis induction), and oleic acid supplemented + FAC; triplicate samples for each condition. We then performed differential gene expression analysis across all 4 conditions to assess for transcriptomic changes.