The Role of Monounsaturated Fatty Acids in Ferroptosis

Exogenous monounsaturated fatty acids (MUFAs) such as oleate (18:1 n-9) protect cells from ferroptotic cell death, contributing to cancer cells' metastatic potential in vivo. Understanding how MUFAs prevent ferroptosis is critical for developing new anti-cancer therapeutics that target this non-apoptotic cell death process. A diversity of MUFAs with varying chain lengths and double bond positions are synthesized in human cells and found in human diets. It is presently unclear which MUFAs can inhibit ferroptosis, and whether all those that are protective act through the same mechanism. To investigate, we have screened a library of structurally distinct MUFA species for their ability to inhibit ferroptosis under various conditions. We find that protection against ferroptosis is MUFA structure-specific, with only certain species being able to protect from ferroptosis. Further investigation indicates that, in response to a pro-ferroptotic stimulus, protective MUFAs can inhibit the formation of toxic lipid reactive oxygen species while non-protective MUFAs are unable to do so. Interestingly, some non-protective MUFAs nonetheless appear to enter the cells and become activated. Thus, we posit that enzymes necessary for MUFA-mediated ferroptosis protection specifically activate and incorporate only certain protective MUFAs into membrane phospholipids. Further characterization of the MUFA metabolic pathway will inform endeavors to synthesize potent ferroptosis inducers that overcome the protective nature of MUFAs in ferroptosis in vivo.