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-𝛂 antagonist), as well as in Caenorhabditis elegans lacking the nuclear hormone receptor NHR-49 (a PPAR-𝛂 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. 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.