{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:36:26Z","timestamp":1792503386375,"version":"4.5.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Struct Mol Biol"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR\u2013Cas9 screens using a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase and flavin adenine dinucleotide (FAD) synthase, enzymes that are essential for synthesizing FAD from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for both FSP1 activity and stability. FAD deficiency and mutations blocking FSP1\u2013FAD binding triggered FSP1 degradation through a ubiquitin\u2013proteasome pathway involving the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance, with implications for therapeutic strategies targeting FSP1 in cancer.<\/jats:p>","DOI":"10.1038\/s41594-026-01759-x","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T10:02:06Z","timestamp":1773396126000},"page":"525-536","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis"],"prefix":"10.1038","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6499-8592","authenticated-orcid":false,"given":"Kirandeep K.","family":"Deol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2530-5519","authenticated-orcid":false,"given":"Cynthia A.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney J.","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J.","family":"Delaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Al-Farhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa J.","family":"Mathiowetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody E.","family":"Doubravsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-745X","authenticated-orcid":false,"given":"Derek A.","family":"Pratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7751-8316","authenticated-orcid":false,"given":"James A.","family":"Olzmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"1759_CR1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1146\/annurev-biochem-052521-033527","volume":"93","author":"Z Li","year":"2024","unstructured":"Li, Z., Lange, M., Dixon, S. J. & Olzmann, J. A. Lipid quality control and ferroptosis: from concept to mechanism. Annu. Rev. Biochem. 93, 499\u2013528 (2024).","journal-title":"Annu. Rev. Biochem."},{"key":"1759_CR2","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/s41580-024-00703-5","volume":"25","author":"SJ Dixon","year":"2024","unstructured":"Dixon, S. J. & Olzmann, J. A. The cell biology of ferroptosis. Nat. Rev. Mol. Cell Biol. 25, 424\u2013442 (2024).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1759_CR3","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","volume":"22","author":"X Jiang","year":"2021","unstructured":"Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266\u2013282 (2021).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"1759_CR4","doi-asserted-by":"publisher","first-page":"103211","DOI":"10.1016\/j.redox.2024.103211","volume":"75","author":"C Berndt","year":"2024","unstructured":"Berndt, C. et al. Ferroptosis in health and disease. Redox Biol 75, 103211 (2024).","journal-title":"Redox Biol"},{"key":"1759_CR5","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","volume":"149","author":"SJ Dixon","year":"2012","unstructured":"Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060\u20131072 (2012).","journal-title":"Cell"},{"key":"1759_CR6","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","volume":"156","author":"WS Yang","year":"2014","unstructured":"Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317\u2013331 (2014).","journal-title":"Cell"},{"key":"1759_CR7","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1038\/ncb3064","volume":"16","author":"JP Friedmann Angeli","year":"2014","unstructured":"Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180\u20131191 (2014).","journal-title":"Nat. Cell Biol."},{"key":"1759_CR8","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1038\/s41556-024-01425-8","volume":"26","author":"T Nakamura","year":"2024","unstructured":"Nakamura, T. & Conrad, M. Exploiting ferroptosis vulnerabilities in cancer. Nat. Cell Biol. 26, 1407\u20131419 (2024).","journal-title":"Nat. Cell Biol."},{"key":"1759_CR9","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41568-022-00459-0","volume":"22","author":"G Lei","year":"2022","unstructured":"Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 22, 381\u2013396 (2022).","journal-title":"Nat. Rev. Cancer"},{"key":"1759_CR10","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1038\/s43018-025-01037-7","volume":"6","author":"JM Ubellacker","year":"2025","unstructured":"Ubellacker, J. M. & Dixon, S. J. Prospects for ferroptosis therapies in cancer. Nat. Cancer 6, 1326\u20131336 (2025).","journal-title":"Nat. Cancer"},{"key":"1759_CR11","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/nature24297","volume":"551","author":"MJ Hangauer","year":"2017","unstructured":"Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247\u2013250 (2017).","journal-title":"Nature"},{"key":"1759_CR12","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nature23007","volume":"547","author":"VS Viswanathan","year":"2017","unstructured":"Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453\u2013457 (2017).","journal-title":"Nature"},{"key":"1759_CR13","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1038\/s41556-024-01464-1","volume":"26","author":"A Schwab","year":"2024","unstructured":"Schwab, A. et al. Zeb1 mediates EMT\/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nat. Cell Biol. 26, 1470\u20131481 (2024).","journal-title":"Nat. Cell Biol."},{"key":"1759_CR14","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.cell.2024.10.047","volume":"188","author":"Y Wang","year":"2025","unstructured":"Wang, Y. et al. ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization. Cell 188, 412\u2013429 (2025).","journal-title":"Cell"},{"key":"1759_CR15","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41586-019-1707-0","volume":"575","author":"S Doll","year":"2019","unstructured":"Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693\u2013698 (2019).","journal-title":"Nature"},{"key":"1759_CR16","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/s41586-019-1705-2","volume":"575","author":"K Bersuker","year":"2019","unstructured":"Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688\u2013692 (2019).","journal-title":"Nature"},{"key":"1759_CR17","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/s41586-022-05022-3","volume":"608","author":"E Mishima","year":"2022","unstructured":"Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778\u2013783 (2022).","journal-title":"Nature"},{"key":"1759_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36446-8","volume":"14","author":"D-Y Jin","year":"2023","unstructured":"Jin, D.-Y. et al. A genome-wide CRISPR\u2013Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase. Nat. Commun. 14, 828 (2023).","journal-title":"Nat. Commun."},{"key":"1759_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29905-1","volume":"13","author":"P Koppula","year":"2022","unstructured":"Koppula, P. et al. A targetable CoQ\u2013FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat. Commun. 13, 2206 (2022).","journal-title":"Nat. Commun."},{"key":"1759_CR20","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1016\/j.chembiol.2023.04.007","volume":"30","author":"JM Hendricks","year":"2023","unstructured":"Hendricks, J. M. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol. 30, 1090\u20131103 (2023).","journal-title":"Cell Chem. Biol."},{"key":"1759_CR21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2505197122","volume":"122","author":"S Zhang","year":"2025","unstructured":"Zhang, S. et al. Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1. Proc. Natl Acad. Sci. USA 122, e2505197122 (2025).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1759_CR22","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1038\/s41594-023-01136-y","volume":"30","author":"T Nakamura","year":"2023","unstructured":"Nakamura, T. et al. Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nat. Struct. Mol. Biol. 30, 1806\u20131815 (2023).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"1759_CR23","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/s41586-023-06255-6","volume":"619","author":"T Nakamura","year":"2023","unstructured":"Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371\u2013377 (2023).","journal-title":"Nature"},{"key":"1759_CR24","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/s41556-023-01314-6","volume":"26","author":"W Cui","year":"2024","unstructured":"Cui, W. et al. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition. Nat. Cell Biol. 26, 124\u2013137 (2024).","journal-title":"Nat. Cell Biol."},{"key":"1759_CR25","doi-asserted-by":"publisher","first-page":"eaea3703","DOI":"10.1126\/sciadv.aea3703","volume":"12","author":"JG Castillo","year":"2026","unstructured":"Castillo, J. G. Selective disruption of lipid peroxide homeostasis in intratumoral regulatory T cells by targeting FSP1 enhances cancer immunity. Sci. Adv. 12, eaea3703 (2026).","journal-title":"Sci. Adv."},{"key":"1759_CR26","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41586-025-09710-8","volume":"649","author":"K Wu","year":"2026","unstructured":"Wu, K. et al. Targeting FSP1 triggers ferroptosis in lung cancer. Nature 649, 487\u2013495 (2026).","journal-title":"Nature"},{"key":"1759_CR27","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41586-025-09709-1","volume":"649","author":"M Palma","year":"2026","unstructured":"Palma, M. et al. Lymph node environment drives FSP1 targetability in metastasizing melanoma. Nature 649, 477\u2013486 (2026).","journal-title":"Nature"},{"key":"1759_CR28","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41556-025-01849-w","volume":"28","author":"CA Harris","year":"2026","unstructured":"Harris, C. A. & Olzmann, J. A. In vivo models bring FSP1 inhibitors to life. Nat. Cell Biol. 28, 6\u20137 (2026).","journal-title":"Nat. Cell Biol."},{"key":"1759_CR29","doi-asserted-by":"publisher","first-page":"4075","DOI":"10.1038\/s41388-025-03562-2","volume":"44","author":"S Salem","year":"2025","unstructured":"Salem, S. et al. Targeting FSP1 to induce ferroptosis in chromophobe renal cell carcinoma. Oncogene 44, 4075\u20134086 (2025).","journal-title":"Oncogene"},{"key":"1759_CR30","doi-asserted-by":"publisher","first-page":"1902","DOI":"10.1038\/s41556-025-01790-y","volume":"27","author":"M Lange","year":"2025","unstructured":"Lange, M. et al. FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis. Nat. Cell Biol. 27, 1902\u20131913 (2025).","journal-title":"Nat. Cell Biol."},{"key":"1759_CR31","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.devcel.2017.11.020","volume":"44","author":"K Bersuker","year":"2018","unstructured":"Bersuker, K. et al. A Proximity labeling strategy provides insights into the composition and dynamics of lipid droplet proteomes. Dev. Cell 44, 97\u2013112 (2018).","journal-title":"Dev. Cell"},{"key":"1759_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15178","volume":"8","author":"DW Morgens","year":"2017","unstructured":"Morgens, D. W. et al. Genome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens. Nat. Commun. 8, 15178 (2017).","journal-title":"Nat. Commun."},{"key":"1759_CR33","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1038\/nbt.3567","volume":"34","author":"DW Morgens","year":"2016","unstructured":"Morgens, D. W., Deans, R. M., Li, A. & Bassik, M. C. Systematic comparison of CRISPR\/Cas9 and RNAi screens for essential genes. Nat. Biotechnol. 34, 634\u2013636 (2016).","journal-title":"Nat. Biotechnol."},{"key":"1759_CR34","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.cell.2013.01.030","volume":"152","author":"MC Bassik","year":"2013","unstructured":"Bassik, M. C. et al. A systematic mammalian genetic interaction map reveals pathways underlying ricin susceptibility. Cell 152, 909\u2013922 (2013).","journal-title":"Cell"},{"key":"1759_CR35","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/j.celrep.2020.01.013","volume":"30","author":"MM Dubreuil","year":"2020","unstructured":"Dubreuil, M. M. et al. Systematic identification of regulators of oxidative stress reveals non-canonical roles for peroxisomal import and the pentose phosphate pathway. Cell Rep. 30, 1417\u20131433 (2020).","journal-title":"Cell Rep."},{"key":"1759_CR36","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nbt.3834","volume":"35","author":"K Han","year":"2017","unstructured":"Han, K. et al. Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nat. Biotechnol. 35, 463\u2013474 (2017).","journal-title":"Nat. Biotechnol."},{"key":"1759_CR37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118646119","volume":"119","author":"GC Forcina","year":"2022","unstructured":"Forcina, G. C. et al. Ferroptosis regulation by the NGLY1\/NFE2L1 pathway. Proc. Natl Acad. Sci. USA 119, e2118646119 (2022).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1759_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101436","volume":"57","author":"S Kotschi","year":"2022","unstructured":"Kotschi, S. et al. NFE2L1-mediated proteasome function protects from ferroptosis. Mol. Metab. 57, 101436 (2022).","journal-title":"Mol. Metab."},{"key":"1759_CR39","doi-asserted-by":"publisher","first-page":"18131","DOI":"10.1074\/jbc.RA119.009591","volume":"294","author":"P Liu","year":"2019","unstructured":"Liu, P. et al. Differential and overlapping targets of the transcriptional regulators NRF1, NRF2, and NRF3 in human cells. J. Biol. Chem. 294, 18131\u201318149 (2019).","journal-title":"J. Biol. Chem."},{"key":"1759_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107583","volume":"300","author":"MB Murray","year":"2024","unstructured":"Murray, M. B. & Dixon, S. J. Ferroptosis regulation by Cap\u2019n\u2019collar family transcription factors. J. Biol. Chem. 300, 107583 (2024).","journal-title":"J. Biol. Chem."},{"key":"1759_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0116-z","volume":"50","author":"R Ree","year":"2018","unstructured":"Ree, R., Varland, S. & Arnesen, T. Spotlight on protein N-terminal acetylation. Exp. Mol. Med. 50, 1\u201313 (2018).","journal-title":"Exp. Mol. Med."},{"key":"1759_CR42","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1126\/science.1183147","volume":"327","author":"C-S Hwang","year":"2010","unstructured":"Hwang, C.-S., Shemorry, A. & Varshavsky, A. N-terminal acetylation of cellular proteins creates specific degradation signals. Science 327, 973\u2013977 (2010).","journal-title":"Science"},{"key":"1759_CR43","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1016\/j.celrep.2019.01.043","volume":"26","author":"JY Cao","year":"2019","unstructured":"Cao, J. Y. et al. A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep. 26, 1544\u20131556 (2019).","journal-title":"Cell Rep."},{"key":"1759_CR44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42342-y","volume":"14","author":"S Varland","year":"2023","unstructured":"Varland, S. et al. N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity. Nat. Commun. 14, 6774 (2023).","journal-title":"Nat. Commun."},{"key":"1759_CR45","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.molcel.2018.11.015","volume":"73","author":"DE Leto","year":"2019","unstructured":"Leto, D. E. et al. Genome-wide CRISPR analysis identifies substrate-specific conjugation modules in er-associated degradation. Mol. Cell 73, 377\u2013389 (2019).","journal-title":"Mol. Cell"},{"key":"1759_CR46","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1074\/mcp.M114.042168","volume":"14","author":"JH Hong","year":"2015","unstructured":"Hong, J. H. et al. KCMF1 (potassium channel modulatory factor 1) links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase 4) and lysosome-mediated degradation. Mol. Cell. Proteomics 14, 674\u2013685 (2015).","journal-title":"Mol. Cell. Proteomics"},{"key":"1759_CR47","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1016\/j.cell.2017.09.040","volume":"171","author":"RG Yau","year":"2017","unstructured":"Yau, R. G. et al. Assembly and function of heterotypic ubiquitin chains in cell-cycle and protein quality control. Cell 171, 918\u2013933 (2017).","journal-title":"Cell"},{"key":"1759_CR48","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1038\/s41586-025-09074-z","volume":"643","author":"Z Yang","year":"2025","unstructured":"Yang, Z. et al. Molecular basis of SIFI activity in the integrated stress response. Nature 643, 1117\u20131126 (2025).","journal-title":"Nature"},{"key":"1759_CR49","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1038\/s41586-023-06985-7","volume":"626","author":"DL Haakonsen","year":"2024","unstructured":"Haakonsen, D. L. et al. Stress response silencing by an E3 ligase mutated in neurodegeneration. Nature 626, 874\u2013880 (2024).","journal-title":"Nature"},{"key":"1759_CR50","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.molcel.2014.05.025","volume":"55","author":"MC Rodrigo-Brenni","year":"2014","unstructured":"Rodrigo-Brenni, M. C., Gutierrez, E. & Hegde, R. S. Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Mol. Cell 55, 227\u2013237 (2014).","journal-title":"Mol. Cell"},{"key":"1759_CR51","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1016\/j.cmet.2023.06.014","volume":"35","author":"X Yang","year":"2023","unstructured":"Yang, X. et al. Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. Cell Metab. 35, 1474\u20131490.e8 (2023).","journal-title":"Cell Metab."},{"key":"1759_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51996-1","volume":"15","author":"J Tschuck","year":"2024","unstructured":"Tschuck, J. et al. Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development. Nat. Commun. 15, 7611 (2024).","journal-title":"Nat. Commun."},{"key":"1759_CR53","doi-asserted-by":"publisher","first-page":"12156","DOI":"10.1073\/pnas.1611994113","volume":"113","author":"A Mart\u00ednez-Lim\u00f3n","year":"2016","unstructured":"Mart\u00ednez-Lim\u00f3n, A. et al. Recognition of enzymes lacking bound cofactor by protein quality control. Proc. Natl Acad. Sci. USA 113, 12156\u201312161 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1759_CR54","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nchembio.1986","volume":"12","author":"MG Rees","year":"2016","unstructured":"Rees, M. G. et al. Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nat. Chem. Biol. 12, 109\u2013116 (2016).","journal-title":"Nat. Chem. Biol."},{"key":"1759_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-024-00723-7","volume":"10","author":"H Lan","year":"2024","unstructured":"Lan, H. et al. Structural insight into 6-OH-FAD-dependent activation of hFSP1 for ferroptosis suppression. Cell Discov. 10, 88 (2024).","journal-title":"Cell Discov."},{"key":"1759_CR56","first-page":"e479","volume":"5","author":"S Feng","year":"2024","unstructured":"Feng, S. et al. The crystal structure of human ferroptosis suppressive protein 1 in complex with flavin adenine dinucleotide and nicotinamide adenine nucleotide. MedComm. e479 5, e479 (2024).","journal-title":"e479"},{"key":"1759_CR57","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1038\/s41422-023-00879-z","volume":"33","author":"S Zhang","year":"2023","unstructured":"Zhang, S. et al. FSP1 oxidizes NADPH to suppress ferroptosis. Cell Res. 33, 967\u2013970 (2023).","journal-title":"Cell Res."},{"key":"1759_CR58","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.molcel.2019.12.002","volume":"77","author":"HP Nguyen","year":"2020","unstructured":"Nguyen, H. P. et al. Aifm2, a NADH oxidase, supports robust glycolysis and is required for cold- and diet-induced thermogenesis. Mol. Cell 77, 600\u2013617 (2020).","journal-title":"Mol. Cell"},{"key":"1759_CR59","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E23-08-0336","volume":"35","author":"C Riepe","year":"2024","unstructured":"Riepe, C. et al. Small-molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states. Mol. Biol. Cell 35, ar15 (2024).","journal-title":"Mol. Biol. Cell"},{"key":"1759_CR60","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.molcel.2012.05.049","volume":"47","author":"O Moscovitz","year":"2012","unstructured":"Moscovitz, O. et al. A mutually inhibitory feedback loop between the 20S proteasome and its regulator, NQO1. Mol. Cell 47, 76\u201386 (2012).","journal-title":"Mol. Cell"},{"key":"1759_CR61","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/j.cell.2012.08.005","volume":"150","author":"F Mattiroli","year":"2012","unstructured":"Mattiroli, F. et al. RNF168 ubiquitinates K13-15 on H2A\/H2AX to drive DNA damage signaling. Cell 150, 1182\u20131195 (2012).","journal-title":"Cell"},{"key":"1759_CR62","doi-asserted-by":"publisher","unstructured":"Garg, A. et al. Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease. Cell https:\/\/doi.org\/10.1016\/j.cell.2026.01.022 (2026).","DOI":"10.1016\/j.cell.2026.01.022"},{"key":"1759_CR63","doi-asserted-by":"publisher","unstructured":"Skafar, V. et al. Riboflavin metabolism shapes FSP1-driven ferroptosis resistance. Nat. Cell Biol. https:\/\/doi.org\/10.1038\/s41556-025-01856-x (2026).","DOI":"10.1038\/s41556-025-01856-x"},{"key":"1759_CR64","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2020.105899","volume":"132","author":"M Mereis","year":"2021","unstructured":"Mereis, M. et al. Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies. Int. J. Biochem. Cell Biol. 132, 105899 (2021).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"1759_CR65","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1038\/s41388-024-02949-x","volume":"43","author":"W Xie","year":"2024","unstructured":"Xie, W. et al. RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis. Oncogene 43, 1463\u20131475 (2024).","journal-title":"Oncogene"},{"key":"1759_CR66","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2023.102201","volume":"4","author":"AJ Mathiowetz","year":"2023","unstructured":"Mathiowetz, A. J., Roberts, M. A., Morgens, D. W., Olzmann, J. A. & Li, Z. Protocol for performing pooled CRISPR\u2013Cas9 loss-of-function screens. STAR Protoc. 4, 102201 (2023).","journal-title":"STAR Protoc."},{"key":"1759_CR67","doi-asserted-by":"publisher","first-page":"1594","DOI":"10.1016\/j.chembiol.2019.09.007","volume":"26","author":"R Shah","year":"2019","unstructured":"Shah, R., Farmer, L. A., Zilka, O., Van Kessel, A. T. M. & Pratt, D. A. Beyond DPPH: use of fluorescence-enabled inhibited autoxidation to predict oxidative cell death rescue. Cell Chem. Biol. 26, 1594\u20131607 (2019).","journal-title":"Cell Chem. Biol."}],"container-title":["Nature Structural &amp; Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41594-026-01759-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41594-026-01759-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41594-026-01759-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T19:02:28Z","timestamp":1774292548000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41594-026-01759-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":67,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["1759"],"URL":"https:\/\/doi.org\/10.1038\/s41594-026-01759-x","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.08.05.668752","asserted-by":"object"}]},"ISSN":["1545-9993","1545-9985"],"issn-type":[{"value":"1545-9993","type":"print"},{"value":"1545-9985","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"8 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"J.A.O. has patent applications related to ferroptosis. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}