{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:55:00Z","timestamp":1790596500817,"version":"4.1.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    Ewing sarcoma tumors are defined by chromosomal translocations fusing\n                    <jats:italic>EWSR1<\/jats:italic>\n                    to ETS family genes, most commonly\n                    <jats:italic>FLI1<\/jats:italic>\n                    . The resulting EWS::FLI1 fusion oncoprotein drives tumorigenesis while simultaneously generating unique metabolic and molecular dependencies that may be exploited for Ewing sarcoma\u2013specific therapies. Through analysis of the Cancer Dependency Map (DepMap, Broad Institute), we identified that Ewing sarcoma cell lines exhibit selective sensitivity to loss of genes regulating selenium metabolism compared to other cancer lineages. Ewing sarcoma cells are similarly sensitive to knockout of glutathione peroxidase 4 (GPX4), a selenoprotein that suppresses ferroptosis, a form of regulated, iron-dependent cell death characterized by the lethal accumulation of lipid peroxides. Using pharmacological inhibitors and targeted degraders of GPX4, as well as genetic knockout approaches, we demonstrate that Ewing sarcoma cells are selectively vulnerable to GPX4 loss or inhibition. We further identify ferroptosis suppressor protein 1 (FSP1) as a modulator of ferroptotic sensitivity in Ewing sarcoma, with FSP1 expression level serving as a determinant of the magnitude of ferroptotic response. Together, these findings establish ferroptosis as a targetable vulnerability in Ewing sarcoma, define GPX4 and FSP1 as key regulators of ferroptotic sensitivity in this disease, and provide a mechanistic rationale for therapeutic strategies targeting the ferroptosis defense axis in Ewing sarcoma tumors.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1945631","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:54:55Z","timestamp":1790592895000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting GPX4 and FSP1 to exploit ferroptotic vulnerability in Ewing sarcoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Mian T.","family":"Mhindu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology\/Oncology, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacia L.","family":"Koppenhafer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology\/Oncology, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mason G.","family":"Lyons","sequence":"additional","affiliation":[{"name":"University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.O.","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology\/Oncology, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology\/Oncology, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0003-x","article-title":"Ewing sarcoma","volume":"4","author":"Gr\u00fcnewald","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.41.5703","article-title":"Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children\u2019s Oncology Group","volume":"30","author":"Womer","year":"2012","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2028910","article-title":"Ewing\u2019s sarcoma","volume":"384","author":"Riggi","year":"2021","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1248753","article-title":"Ewing sarcoma from molecular biology to the clinic","volume":"11","author":"Dupuy","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2014.947963","article-title":"Blocking the road, stopping the engine or killing the driver? Advances in targeting EWS\/FLI-1 fusion in Ewing sarcoma as novel therapy","volume":"18","author":"Kovar","year":"2014","journal-title":"Expert Opin Ther Targets"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103211","article-title":"Ferroptosis in health and disease","volume":"75","author":"Berndt","year":"2024","journal-title":"Redox Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-024-05009-w","article-title":"Important molecular mechanisms in ferroptosis","volume":"480","author":"Lai","year":"2025","journal-title":"Mol Cell Biochem"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00459-0","article-title":"Targeting ferroptosis as a vulnerability in cancer","volume":"22","author":"Lei","year":"2022","journal-title":"Nat Rev Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3390\/biomedicines10040891","article-title":"The selenoprotein glutathione peroxidase 4: from molecular mechanisms to novel therapeutic opportunities","volume":"10","author":"Weaver","year":"2022","journal-title":"Biomedicines"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2026.01.008","article-title":"Decoding GPX4 regulation in ferroptosis: mechanisms and therapeutic implications","volume":"32","author":"Chen","year":"2026","journal-title":"Trends Mol Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.3390\/ijms24021607","article-title":"Prospects for anti-tumor mechanism and potential clinical application based on glutathione peroxidase 4 mediated ferroptosis","volume":"24","author":"Chen","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"312","DOI":"10.3390\/antiox15030312","article-title":"The role of Se-containing glutathione peroxidases and thioredoxin reductases in oncogenesis: Expression paradoxes and therapeutic prospects","volume":"15","author":"Varlamova","year":"2026","journal-title":"Antioxidants (Basel)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09710-8","article-title":"Targeting FSP1 triggers ferroptosis in lung cancer","volume":"649","author":"Wu","year":"2026","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2026.118151","article-title":"FSP1, a key ferroptosis suppressor with therapeutic potential","volume":"251","author":"Bai","year":"2026","journal-title":"Biochem Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2023.05.013","article-title":"FSP1: a key regulator of ferroptosis","volume":"29","author":"Li","year":"2023","journal-title":"Trends Mol Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05022-3","article-title":"A non-canonical vitamin K cycle is a potent ferroptosis suppressor","volume":"608","author":"Mishima","year":"2022","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1707-0","article-title":"FSP1 is a glutathione-independent ferroptosis suppressor","volume":"575","author":"Doll","year":"2019","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-1778","article-title":"Polyamine depletion by D,L-\u03b1-difluoromethylornithine inhibits Ewing sarcoma metastasis by inducing ferroptosis","volume":"31","author":"Offenbacher","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2026.06.026","article-title":"Shogaol triggers apoptosis and ferroptosis in Ewing sarcoma by targeting the polo-like kinase 1\/nucleophosmin 1 axis","volume":"254","author":"Wu","year":"2026","journal-title":"Free Radic Biol Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5225","DOI":"10.3390\/cancers15215225","article-title":"Carbonic anhydrase inhibitors induce ferroptosis through inhibition of AKT\/FTH1 signaling in Ewing sarcoma tumor cells","volume":"15","author":"Fayzullina","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B24","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/s41419-024-06485-0","article-title":"AURKA inhibition induces Ewing\u2019s sarcoma apoptosis and ferroptosis through NPM1\/YAP1 axis","volume":"15","author":"Chen","year":"2024","journal-title":"Cell Death Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/s41419-024-06882-5","article-title":"SETD8 inhibits apoptosis and ferroptosis of Ewing\u2019s sarcoma through YBX1\/RAC3 axis","volume":"15","author":"Chen","year":"2024","journal-title":"Cell Death Dis"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3802","DOI":"10.1038\/s41467-026-70449-5","article-title":"Proteomic landscape of Ewing sarcoma primary tumors and metastases","volume":"17","author":"Gordon","year":"2026","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2423","DOI":"10.1038\/s41467-020-16244-2","article-title":"Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma","volume":"11","author":"Marchetto","year":"2020","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-17-0182","article-title":"EWS\/FLI is a master regulator of metabolic reprogramming in Ewing sarcoma","volume":"15","author":"Tanner","year":"2017","journal-title":"Mol Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.262","article-title":"GSTM4 is a microsatellite-containing EWS\/FLI target involved in Ewing\u2019s sarcoma oncogenesis and therapeutic resistance","volume":"28","author":"Luo","year":"2009","journal-title":"Oncogene"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1394653","article-title":"Auranofin and reactive oxygen species inhibit protein synthesis and regulate the level of the PLK1 protein in Ewing sarcoma cells","volume":"14","author":"Haight","year":"2024","journal-title":"Front Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1586\/era.10.224","article-title":"Oxidative stress and therapeutic opportunities: focus on the Ewing\u2019s sarcoma family of tumors","volume":"11","author":"Smith","year":"2011","journal-title":"Expert Rev Anticancer Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2050","article-title":"p38MAPK-dependent sensitivity of Ewing\u2019s sarcoma family of tumors to fenretinide-induced cell death","volume":"11","author":"Myatt","year":"2005","journal-title":"Clin Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/s41568-024-00763-x","article-title":"The present and future of the Cancer Dependency Map","volume":"25","author":"Arafeh","year":"2025","journal-title":"Nat Rev Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-25-0058","article-title":"Histone deacetylase inhibitors target DNA replication regulators and replication stress in Ewing sarcoma cells","volume":"5","author":"Koppenhafer","year":"2025","journal-title":"Cancer Res Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: a graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: integrating viruses and cellular organisms","volume":"49","author":"Kanehisa","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: an R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/978-1-0716-3433-2_6","article-title":"Probing lipid peroxidation in ferroptosis: Emphasizing the utilization of C11-BODIPY-based protocols","volume":"2712","author":"Dai","year":"2023","journal-title":"Methods Mol Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-0247-8_11","article-title":"Detection of ferroptosis by BODIPYTM 581\/591 C11","volume":"2108","author":"Martinez","year":"2020","journal-title":"Methods Mol Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-4207","article-title":"Lipid composition alters ferroptosis sensitivity","volume":"85","author":"Park","year":"2025","journal-title":"Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115343","article-title":"Discovery of ML210-based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells","volume":"254","author":"Wang","year":"2023","journal-title":"Eur J Med Chem"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01360-8","article-title":"A guideline on the molecular ecosystem regulating ferroptosis","volume":"26","author":"Dai","year":"2024","journal-title":"Nat Cell Biol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3064","article-title":"Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice","volume":"16","author":"Friedmann Angeli","year":"2014","journal-title":"Nat Cell Biol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017963","article-title":"NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels","volume":"6","author":"Haefeli","year":"2011","journal-title":"PloS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.cell.2017.11.048","article-title":"Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis","volume":"172","author":"Ingold","year":"2018","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/s41419-026-08466-x","article-title":"Selenomethionine as a dual-mechanism ferroptosis inhibitor: selenium-supply-driven GPX4 biosynthesis beyond transsulfuration and reductive-capacity-mediated ROS scavenging independent of GPX4 activity","volume":"17","author":"Xia","year":"2026","journal-title":"Cell Death Dis"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-022-01033-3","article-title":"Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability","volume":"18","author":"Li","year":"2022","journal-title":"Nat Chem Biol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"7261","DOI":"10.3390\/ijms25137261","article-title":"Selenium discrepancies in fetal bovine serum: impact on cellular selenoprotein expression","volume":"25","author":"Parant","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.5c00447","article-title":"N\u2019-(1-Phenylethylidene)benzohydrazide cytotoxicity is lysine-specific demethylase 1 independent and linked to iron-sulfur cluster disruption in Ewing sarcoma","volume":"8","author":"Sherman","year":"2025","journal-title":"ACS Pharmacol Transl Sci"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1186\/s12885-020-07668-6","article-title":"Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication","volume":"20","author":"Waters","year":"2020","journal-title":"BMC Cancer"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11416","article-title":"Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma","volume":"7","author":"Goss","year":"2016","journal-title":"Oncotarget"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03539-7","article-title":"DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer","volume":"593","author":"Mao","year":"2021","journal-title":"Nature"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2024.05.006","article-title":"Targeting GPX4 in ferroptosis and cancer: chemical strategies and challenges","volume":"45","author":"Liu","year":"2024","journal-title":"Trends Pharmacol Sci"},{"key":"B55","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s41420-022-01297-7","article-title":"Recent progress in ferroptosis: inducers and inhibitors","volume":"8","author":"Du","year":"2022","journal-title":"Cell Death Discov"},{"key":"B56","doi-asserted-by":"publisher","first-page":"6452","DOI":"10.3390\/ijms26136452","article-title":"Emerging therapeutic strategies targeting GPX4-mediated ferroptosis in head and neck cancer","volume":"26","author":"Lee","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B57","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s43556-026-00416-5","article-title":"Targeting ferroptosis in cancer: from mechanistic insights to therapeutic approaches","volume":"7","author":"Wang","year":"2026","journal-title":"Mol BioMed"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1945631\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:54:57Z","timestamp":1790592897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1945631\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":57,"alternative-id":["10.3389\/fonc.2026.1945631"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1945631","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]},"article-number":"1945631"}}