Cell Chemical Biology
Volume 26, Issue 3, 21 March 2019, Pages 420-432.e9
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Article
Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State

https://doi.org/10.1016/j.chembiol.2018.11.016Get rights and content
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Highlights

  • Exogenous MUFAs inhibit ferroptosis in a structure-specific manner

  • MUFAs block lipid ROS accumulation specifically at the plasma membrane

  • Exogenous MUFAs inhibit ferroptosis in an ACSL3-dependent manner

  • Exogenous MUFAs inhibit apoptotic lipotoxicity in an ACSL3-independent manner

Summary

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

ferroptosis
oleate
MUFAs
iron
lipid ROS
cell death
lipotoxicity
GPX4
lipid droplet

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