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. 2025 Mar 20;32(3):408-422.e6.
doi: 10.1016/j.chembiol.2024.09.008. Epub 2024 Oct 22.

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking

Kelly H Sokol  1 , Cameron J Lee  1 , Thomas J Rogers  1 , Althea Waldhart  1 , Abigail E Ellis  2 , Sahithi Madireddy  3 , Samuel R Daniels  4 , Rachel Rae J House  1 , Xinyu Ye  5 , Mary Olesnavich  5 , Amy Johnson  2 , Benjamin R Furness  1 , Ryan D Sheldon  2 , Evan C Lien  6
Affiliations

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking

Kelly H Sokol et al. Cell Chem Biol. .

Abstract

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic and adrenic acid. These PUFAs then accumulate in phospholipids, including ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools contributes to their sensitivity to ferroptosis.

Keywords: cancer; ferroptosis; lipid metabolism; phospholipids; polyunsaturated fatty acids; triglycerides.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

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