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We identified the glucocorticoid receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) as a key negative regulator of radiosensitivity linked to poor prognosis. NR3C1 transcriptionally upregulates the lipid\u2010metabolizing enzyme, acyl\u2010CoA synthetase long\u2010chain family member 4 (ACSL4), thereby enhancing cell proliferation, migration, and radioresistance. High ACSL4 expression sensitizes cells to ferroptosis inducers that amplify lipid peroxidation and restore radiosensitivity. Using the clinically applicable ferroptosis inducer, dihydroartemisinin (DHA), we found that DHA synergizes with ACSL4 to trigger ferroptosis, sensitizing radioresistant cells and xenografts to radiation. This effect was characterized by elevated lipid peroxidation and was reversed by the ferroptosis inhibitor deferoxamine. Collectively, our study revealed that the NR3C1\u2010ACSL4 axis regulates lipid peroxidation and promotes radioresistance. Targeting this axis with DHA and using ACSL4 as a biomarker represents a promising preclinical strategy to overcome radioresistance in prostate cancer, pending further clinical validation.<\/jats:p>","DOI":"10.1111\/cas.70479","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T19:45:42Z","timestamp":1784835942000},"page":"2953-2966","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the\n                    <scp>NR3C1<\/scp>\n                    \u2010\n                    <scp>ACSL4<\/scp>\n                    Axis Triggers Ferroptosis to Overcome Radioresistance in Prostate Cancer"],"prefix":"10.1111","volume":"117","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Oncology Nanjing First Hospital, Nanjing Medical University  Nanjing P. R. 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