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Disulfidptosis, a recently identified form of cell death characterized by cytoskeletal collapse under conditions of glucose deprivation and elevated SLC7A11 expression, presents a potential novel avenue for intervention. In this study, we integrated TCGA and GEO data and employed machine learning techniques to identify disulfidptosis-related genes in prostate cancer. Functional analyses using SLC7A11-overexpressing and knockout cell lines demonstrated that SLC7A11 promotes cellular proliferation, migration, and invasion, while its overexpression under glucose-starved conditions triggers disulfidptosis, also inducible pharmacologically using the glucose uptake inhibitor BAY-876. Through CUT&amp;Tag, ChIP-seq, and luciferase assays, we identified FOXA1 as a key transcriptional regulator of SLC7A11, driven by a super-enhancer located at chr14:37583488\u201337589585. CRISPR-Cas9 deletion of this super-enhancer reduced FOXA1 and SLC7A11 expression, thereby protecting cells from disulfidptosis. These findings highlight the critical role of the SE\/FOXA1\/SLC7A11 regulatory axis in driving both disulfidptosis and tumor progression, suggesting that targeting this pathway, particularly in glucose-deprived tumor environments, may offer promising therapeutic strategies for PCa.<\/jats:p>","DOI":"10.1038\/s41419-025-08227-2","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T01:55:03Z","timestamp":1764726903000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Super-enhancers mediates SLC7A11 via FOXA1 to regulate disulfidptosis in prostate cancer"],"prefix":"10.1038","volume":"17","author":[{"given":"Zhen","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-7781","authenticated-orcid":false,"given":"Zhi-Bin","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7426-6501","authenticated-orcid":false,"given":"Qing-Shui","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6461-7435","authenticated-orcid":false,"given":"Xue-Yi","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-3733","authenticated-orcid":false,"given":"Yong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7909-7025","authenticated-orcid":false,"given":"Ning","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"8227_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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All animal experiments were approved by the Experimental Animal Ethics Committee of Fujian Medical University (Approval No. IACUC FJMU 2022-0617). Throughout the experimental procedures, all animals were housed and cared for in accordance with the institutional guidelines for the care and use of laboratory animals, with efforts made to minimize pain and discomfort.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"63"}}