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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #427428
Research Project: Utilizing Precision Approaches to Refine Dietary Guidance of Americans to Reduce Chronic Disease

Location: Obesity and Metabolism Research

Title: FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis

Author
item LANGE, MIKE - University Of California Berkeley
item WÖLK, MICHELE - University Of California Berkeley
item LI, VIVIAN WEN - University Of California Berkeley
item DOUBRAVSKY, CODY - University Of California Berkeley
item HENDRICKS, JOSEPH - University Of California Berkeley
item KATO, SHUNJI - Tohoku University
item OTOKI, YURIKA - Tohoku University
item STYLER, BENJAMIN - University Of California Berkeley
item JOHNSON, SEAN - University Of California Berkeley
item HARRIS, ABBY CYNTHIA - University Of California Berkeley
item NAKAGAWA, KIYOTAKA - Tohoku University
item SNODGRASS, ISABEL - University Of California, Davis
item Kim, Dohee
item Newman, John
item FEDOROVA, MARIA - Technical University Dresden
item OLZMANN, JAMES - University Of California Berkeley

Submitted to: Nature Cell Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/22/2025
Publication Date: 10/29/2025
Citation: Lange, M., Wölk, M., Li, V., Doubravsky, C.E., Hendricks, J.M., Kato, S., Otoki, Y., Styler, B., Johnson, S., Harris, A., Nakagawa, K., Snodgrass, I.F., Kim, D., Newman, J.W., Fedorova, M., Olzmann, J.A. 2025. FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis. Nature Cell Biology. 27:1902-1913. https://doi.org/10.1038/s41556-025-01790-y.
DOI: https://doi.org/10.1038/s41556-025-01790-y

Interpretive Summary: Lipid droplets are organelles that store and supply lipids based on cellular needs. How lipid droplet lipids are protected from oxidative damage is unknown. We identified a lipid droplet-associated protein, Ferroptosis Suppressor Protein 1 (FSP1), that prevents neutral lipid peroxidation by recycling the antioxidant coenzyme Q10. When FSP1 does not function, if cell are grown in a polyunsaturated fatty acid-rich environment, oxidized lipids accumulate in lipid droplets leading to cell death. This is the first reported mechanism of cell protection that prevents oxidized lipid accumulation in lipid droplets.

Technical Abstract: Lipid droplets (LDs) are organelles that store and supply lipids based on cellular needs. While mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here, we identify LD-localized Ferroptosis Suppressor Protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, polyunsaturated fatty acid (PUFA)-rich triacylglycerols enhance cancer cell sensitivity to FSP1 loss and inducing PUFA-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the buildup of oxidized lipids and induction of ferroptosis.