Riboflavin metabolism shapes FSP1-driven ferroptosis resistance
Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B<sub>2</sub>) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.
Authors
- Biplab Ghosh (ORCID: https://orcid.org/0000-0002-8783-6315)
- Hamed Alborzinia (ORCID: https://orcid.org/0000-0001-6903-3001)
- Jessalyn M. Ubellacker (ORCID: https://orcid.org/0000-0002-7855-9125)
- M. Fedorova
- Kamyar Hadian (ORCID: https://orcid.org/0000-0001-8727-2575)
- Ralf C. Bargou (ORCID: https://orcid.org/0000-0002-1221-7421)
- Marcus Conrad (ORCID: https://orcid.org/0000-0003-1140-5612)
- Ulrich Elling (ORCID: https://orcid.org/0000-0002-4514-2809)
- Hellmut G. Augustin (ORCID: https://orcid.org/0000-0002-7173-4242)
- Bettina Proneth (ORCID: https://orcid.org/0000-0002-4119-9437)
- Martin Eilers (ORCID: https://orcid.org/0000-0002-0376-6533)
- Mayher Kaur (ORCID: https://orcid.org/0009-0007-2097-4063)
- Sebastian Bothe (ORCID: https://orcid.org/0000-0001-6408-6112)
- Svenja Meierjohann (ORCID: https://orcid.org/0000-0002-9058-7196)
- Shibo Sun (ORCID: https://orcid.org/0000-0002-5739-9062)
- Ancély Ferreira dos Santos (ORCID: https://orcid.org/0000-0003-4985-6187)
- Apoorva Mathur
- Jannik Buhr (ORCID: https://orcid.org/0000-0002-9350-2629)
- Vera Skafar
- Camilo Andres Aponte-Santamaria
- Werner Schmitz (ORCID: https://orcid.org/0000-0003-0485-7303)
- Palina Nepachalovich (ORCID: https://orcid.org/0000-0002-3404-9537)
- José Pedro Friedmann Ângeli
- Florêncio Porto Freitas (ORCID: https://orcid.org/0000-0002-0369-4488)
- Izadora de Souza (ORCID: https://orcid.org/0000-0002-6935-7521)
- Mario Palma
- Lars Seufert
- Milena Chaufan
- Zhiyi Chen
- Ariane Nunes-Alves
- Matthias Mack
- Juliane Tschuck
- Merce Donate Castillo
Institutions
- Technische Hochschule Mannheim (DE)
- Institute of Molecular Biotechnology (AT)
- Harvard University (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- University Hospital Heidelberg (DE)
- Helmholtz Zentrum München (DE)
- Comprehensive Cancer Center Mainfranken (DE)
- Universitätsklinikum Würzburg (DE)
- DKFZ-ZMBH Alliance (DE)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- University Hospital Carl Gustav Carus (DE)
- Technische Universität Berlin (DE)
- Technical University of Munich (DE)
- Heidelberg Institute for Theoretical Studies (DE)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2026-03-13
- DOI
- https://doi.org/10.1038/s41556-025-01856-x
- Citations
- 2
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 72.89