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Skafar, V.* ; de Souza, I.* ; Ghosh, B.* ; Ferreira Dos Santos, A.* ; Porto Freitas, F.* ; Chen, Z.* ; Sun, S.* ; Donate Castillo, M.* ; Nepachalovich, P.* ; Seufert, L.* ; Bothe, S.* ; Tschuck, J. ; Mathur, A.* ; Nunes-Alves, A.* ; Buhr, J.* ; Aponte-Santamaría, C.* ; Schmitz, W.* ; Mack, M.* ; Eilers, M.* ; Bargou, R.* ; Chaufan, M.* ; Kaur, M.* ; Palma, M.* ; Ubellacker, J.M.* ; Elling, U.* ; Augustin, H.G.* ; Hadian, K. ; Meierjohann, S.* ; Proneth, B. ; Conrad, M. ; Fedorova, M.* ; Alborzinia, H.* ; Friedmann Angeli, J.P.*

Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.

Nat. Cell Biol. 28, 696-706 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 B2) 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gpx4 ; Riboflavin ; Glutathione ; Lipid Peroxidation ; Reactive Oxygen Species ; Intracellular ; Function (biology) ; Antioxidant ; Phospholipid-hydroperoxide Glutathione Peroxidase; Particle Mesh Ewald; Antioxidant; Inhibition; Mechanisms; Protein; Plasma; Acid
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Zeitschrift Nature Cell Biology
Quellenangaben Band: 28, Heft: 4, Seiten: 696-706 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Heidelberger Platz 3, Berlin, 14197, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
Institute of Metabolism and Cell Death (MCD)