Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State

Cell Chem Biol. 2019 Mar 21;26(3):420-432.e9. doi: 10.1016/j.chembiol.2018.11.016. Epub 2019 Jan 24.


The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.

Keywords: GPX4; MUFAs; cell death; ferroptosis; iron; lipid ROS; lipid droplet; lipotoxicity; oleate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acid / chemistry
  • Arachidonic Acid / metabolism
  • Arachidonic Acid / pharmacology
  • Cell Line
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Coenzyme A Ligases / metabolism
  • Fatty Acids, Monounsaturated / chemistry
  • Fatty Acids, Monounsaturated / metabolism
  • Fatty Acids, Monounsaturated / pharmacology*
  • Ferroptosis / drug effects*
  • Lipid Droplets / chemistry
  • Lipid Droplets / metabolism
  • Lipids / chemistry*
  • Mice
  • Oxidation-Reduction
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
  • Reactive Oxygen Species / chemistry
  • Reactive Oxygen Species / metabolism


  • Fatty Acids, Monounsaturated
  • Lipids
  • Reactive Oxygen Species
  • Arachidonic Acid
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse
  • Acsl3 protein, mouse
  • Coenzyme A Ligases