{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T03:05:31Z","timestamp":1793675131879,"version":"4.5.1"},"posted":{"date-parts":[[2026,3,14]]},"group-title":"Cancer Biology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R01CA286141"],"award-info":[{"award-number":["R01CA286141"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R01GM132491"],"award-info":[{"award-number":["R01GM132491"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["P30CA016087"],"award-info":[{"award-number":["P30CA016087"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Ferroptosis is a cell death mechanism characterized by the accumulation of iron-catalyzed lipid peroxides in membrane lipid acyl chains and subsequent loss of membrane integrity.\n                  <jats:sup>1<\/jats:sup>\n                  Despite thorough investigation of its mechanisms in cultured cells, induction of ferroptosis has unresolved clinical utility in cancer therapy. Here, we systematically evaluate ferroptosis induction via multiple mechanisms, in both cell and tumor models, using focused genetic screens, genetic loss-of-function systems, and pharmacological perturbations. Through this analysis we identify cancer cell line subsets with distinct responses to canonical ferroptosis inducers and suppressors and define the underpinnings of each. Inhibition of central\n                  <jats:italic>in vitro<\/jats:italic>\n                  ferroptosis suppressors GPX4, GCLC, or SLC7A11 across these multiple models fails to impact established tumor growth. In contrast, deficiency in the cytosolic thioredoxin reductase and pharmacologic GCLC inhibition potently induces tumor regression and triggers a form of non-ferroptotic cell death regulated by cystine availability and translation. These analyses further reveal that the principal essential function of environmental cystine in cultured cells is to support selenoprotein function, identified through investigating our finding that \u03b2-mercaptoethanol supports exponential growth in cystine-free conditions. Thus, while ferroptosis activation may be efficacious alone or in combination with other therapies in specific tumor contexts, cell culture systems greatly overestimate the potential anti-cancer effects of ferroptosis induction via the GPX4 axis.\n                <\/jats:p>","DOI":"10.64898\/2026.03.11.711115","type":"posted-content","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T14:30:19Z","timestamp":1773498619000},"source":"Crossref","is-referenced-by-count":1,"title":["Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy"],"prefix":"10.64898","author":[{"given":"Kenji M.","family":"Fujihara","sequence":"first","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Laura & Isaac Perlmutter Cancer Center, New York, NY 10016, USA"},{"name":"Department of Radiation Oncology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azmi","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Laura & Isaac Perlmutter Cancer Center, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behnia","family":"Akbari","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Laura & Isaac Perlmutter Cancer Center, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gutierrez-Perez","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigaci\u00f3n Hospital 12 de Octubre (i+12) & Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Gregory","family":"Francis","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Laura & Isaac Perlmutter Cancer Center, New York, NY 10016, USA"},{"name":"Department of Radiation Oncology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siham","family":"Zentout","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kameng","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cancer Research, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia. Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9283-9978","authenticated-orcid":false,"given":"Nicholas J.","family":"Clemons","sequence":"additional","affiliation":[{"name":"Division of Cancer Research, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia. Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdem M.","family":"Terzi","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA"},{"name":"Laura & Isaac Perlmutter Cancer Center, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Pacold","sequence":"additional","affiliation":[{"name":"Laura & Isaac Perlmutter Cancer Center, New York, NY 10016, USA"},{"name":"Department of Radiation Oncology, New York University Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2401-0030","authenticated-orcid":false,"given":"Richard","family":"Possemato","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University 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