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Ferroptosis offers an attractive strategy for cancer therapy, but classical ferroptosis is iron\u2011dependent. Repurposing approved drugs offers a rapid strategy to identify novel anti\u2011LUAD agents, yet the mechanism by which 4\u2011Hydroxytamoxifen (4\u2011OHT) exerts estrogen receptor\u2013independent anti\u2011tumour effects remains unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed a drug repurposing screen of 950 endogenous metabolites in LUAD cells.<\/jats:p>\n Anti\u2011tumour activity was validated in vitro and in vivo using LUAD cell lines and mouse models. Target identification and mechanistic studies employed LiP\u2011MS, pull\u2010down SPR, CETSA, metabolomics, and enzyme activity assays. Clinical relevance was assessed via tissue microarrays and TCGA analysis. Drug synergy was quantified using the Chou\u2013Talalay method.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 4\u2011OHT inhibited LUAD cell proliferation with IC\n 50<\/jats:sub>\n values of 3.86\u00a0\u00b1\u00a00.26\u00a0\u00b5M to 13.58\u00a0\u00b1\u00a00.55\u00a0\u00b5M independent of estrogen receptor. It triggered noncanonical ferroptosis characterised by GSH depletion (reduced by about 60%), GPX4 downregulation, lipid peroxidation (about 2.5\u2010fold increase), and iron independence. Mechanistically, 4\u2011OHT directly bound AKR1B10 (K\n D<\/jats:sub>\n (M) was 7.98e\u201006) and inhibited its enzymatic activity, leading to ACC1 degradation, lipid deficiency, and accumulation of toxic lipid\u2011derived carbonyls. AKR1B10 knockout abolished 4\u2011OHT\u2011induced cell death, while rescue restored sensitivity. Nanatinostat similarly targeted AKR1B10 and induced the same cell death modality. AKR1B10 upregulation in LUAD tissues correlated with reduced overall survival rates.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n This study demonstrates that 4\u2011OHT directly inhibits AKR1B10 enzymatic activity to induce a noncanonical ferroptosis in LUAD. AKR1B10 overexpression correlates with poor prognosis and chemoresistance in LUAD patients. Nonetheless, AKR1B10 inhibition warrants further investigation as a therapeutic strategy.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n 4\u2011OHT directly inhibits AKR1B10 enzymatic activity to induce noncanonical ferroptosis in LUAD.<\/jats:p>\n <\/jats:list-item>\n \n AKR1B10 sustains LUAD survival by stabilising ACC1 and detoxifying reactive carbonyl species (RCSs).<\/jats:p>\n <\/jats:list-item>\n \n Nanatinostat similarly targets AKR1B10 and elicits the same cell death modality.<\/jats:p>\n <\/jats:list-item>\n \n AKR1B10 overexpression correlates with poor prognosis and chemoresistance in LUAD.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/ctm2.70796","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:18:58Z","timestamp":1788855538000},"source":"Crossref","is-referenced-by-count":0,"title":["4\u2010Hydroxytamoxifen induces a noncanonical ferroptosis in lung adenocarcinoma by targeting AKR1B10"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9666-7413","authenticated-orcid":false,"given":"Hui","family":"Yang","sequence":"first","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Respiratory Diseases Jiangxi Institute of Respiratory Diseases Jiangxi Clinical Research Center for Respiratory Diseases Department of Pulmonary and Critical Care Medicine The First Affiliated Hospital Jiangxi Medical College Nanchang University Nanchang Jiangxi Province P.R. 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