Exogenous Monounsaturated Fatty Acids Suppress Non-Apoptotic Cell Death

The initiation and execution of cell death is regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. Using a high-throughput lipid modulation screen we find that physiological levels of extracellular free fatty acids have diverse effects on non-apoptotic and apoptotic cell death induced by lethal small molecules and natural products. In particular, monounsaturated fatty acids (MUFAs) are found to suppress the non-apoptotic, iron-dependent cell death process of ferroptosis. This protective effect requires acyl-CoA synthetase long-chain family member 3 (ACSL3) and involves suppression of toxic lipid ROS accumulation specifically at the plasma membrane. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but through a genetically distinct mechanism. Thus, MUFAs emerge as key lipid metabolites regulating both non-apoptotic and apoptotic cell death.