Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State

By Leslie Magtanong, Pin-Joe Ko, Milton To, J. Cao, G. Forcina, Amy Tarangelo, Carl C. Ward, Kevin Y. Cho, G. Patti, Daniel K. Nomura and 2 more. Cell Chemical Biology, 2019

987 citations recorded by the source corpus.

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 toxic lipid reactive oxygen species (ROS) accumulation specifically at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. We find that treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to lethal oxidation over several hours, and that this process requires MUFA activation by acyl-CoA synthetase long-chain family member 3 (ACSL3). 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 exogenous MUFAs and ACSL3 activity specifically promote a ferroptosis-resistant cell state.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/9dd0312417f67c9b8bd320f02bd42a4c76ffd532

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Pulmonary and Respiratory Medicine

Citations in the corpus

The cell biology of ferroptosis (2024, positive): “Decreasing the ratio of more oxidizable PUFAs to less oxidizable monounsaturated fatty acids (MUFAs) is sufficient to convert cells from ferroptosis sensitive to ferroptosis resistant 28,98–101 whereas increasing the PUFA to MUFA ratio can have the opposite effect 22,77 .”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “Moreover, monounsaturated fatty acids (MUFAs), such as oleic acid, require ACSL3 in order to exert anti-ferroptotic effects (Magtanong et al., 2019).”
The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “As reported earlier, the levels of PUFAs determine the degree of lipid peroxidation, and the accumulated lipid droplets serve as a reservoir for PUFAs.(29,47) Moreover, oxidized lipids and lipid bodies containing oxidative truncated lipids in DCs can inhibit crosspresentation in cancer.”
Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones (2023, background): “Further, ACSL3 selectively converts MUFAs into MUFA-CoA before their incorporation into PL, which is required for the ferroptosis-suppressing function of MUFA.(35) In agreement with this, ACSL3 knockdown provoked”
Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “46,68,69 ACSL4 and LPCAT3 are responsible for the biosynthesis and esteri ﬁ cation of PUFA-PLs.”