FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis
Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although 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, inducing polyunsaturated fatty acid-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 build-up of oxidized lipids and induction of ferroptosis.
Authors
- Maria Fedorova (ORCID: https://orcid.org/0000-0002-4692-3885)
- Kiyotaka Nakagawa (ORCID: https://orcid.org/0000-0003-3026-7358)
- Yurika Otoki (ORCID: https://orcid.org/0000-0001-9172-2161)
- James A. Olzmann (ORCID: https://orcid.org/0000-0001-7751-8316)
- Shunji Kato (ORCID: https://orcid.org/0000-0003-4659-9541)
- Sean L. Johnson (ORCID: https://orcid.org/0000-0002-7149-6563)
- Joseph M. Hendricks
- Cody E. Doubravsky
- Carolyn Harris
- Michele Wölk (ORCID: https://orcid.org/0000-0001-5558-4582)
- John W. Newman (ORCID: https://orcid.org/0000-0001-9632-6571)
- Isabel F. Snodgrass
- Do‐Hee Kim (ORCID: https://orcid.org/0009-0008-0457-3232)
- Vivian Li (ORCID: https://orcid.org/0000-0003-2971-2610)
- Mike Lange (ORCID: https://orcid.org/0000-0002-4728-9927)
- Benjamin S. Styler (ORCID: https://orcid.org/0000-0002-0458-8230)
Institutions
- Agricultural Research Service (US)
- United States Department of Agriculture (US)
- Tohoku University (JP)
- Western Human Nutrition Research Center (US)
- University Hospital Carl Gustav Carus (DE)
- Technische Universität Dresden (DE)
- University of California, Davis (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s41556-025-01790-y
- Citations
- 13
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 14.45