{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:19:25Z","timestamp":1792685965027,"version":"4.5.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473185"],"award-info":[{"award-number":["82473185"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82202922"],"award-info":[{"award-number":["82202922"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:p>\n                    Androgen receptor (AR) signaling is central to prostate cancer progression, yet resistance to AR-targeted therapies remains a major clinical challenge. Understanding the molecular consequences of AR pathway inhibition is therefore essential for improving therapeutic outcomes. Here, we identify a previously unrecognized link between AR antagonism and cuproptosis, a copper-dependent form of regulated cell death. Using integrated genomic profiling, we find that AR-targeted agents transcriptionally activate the key cuproptosis regulator Ferredoxin-1 (FDX1), thereby rendering prostate cancer cells markedly more susceptible to copper-induced lethality. Mechanistically, ligand-bound AR directly engages\n                    <jats:italic toggle=\"yes\">FDX1<\/jats:italic>\n                    cis-regulatory elements, which are rendered accessible by the pioneer factor GATA2, and drives\n                    <jats:italic toggle=\"yes\">FDX1<\/jats:italic>\n                    upregulation upon AR antagonist exposure. Consistent with this mechanism, FDX1 expression is elevated in clinical prostate cancer samples following androgen deprivation therapy or AR antagonist treatment. Increased FDX1 enhances intracellular Cu\n                    <jats:sup>+<\/jats:sup>\n                    accumulation, destabilizes Fe-S cluster proteins, and disrupts mitochondrial metabolism, establishing a procuproptotic state. Functionally, combining AR antagonists with copper ionophores synergistically induces cuproptosis and potently suppresses tumor growth in AR-positive prostate cancer cells, three-dimensional (3D) spheroids, patient-derived organoids, and xenograft models, with minimal systemic toxicity. This synergy is abolished by FDX1 loss or copper chelation, confirming dependence on AR\u2013FDX1 axis activation. Together, these findings uncover FDX1 as a mechanistic effector of AR pathway inhibition and propose a well-tolerated combination strategy that exploits cuproptosis to improve therapeutic responses in prostate cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2534978123","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T17:36:23Z","timestamp":1777656983000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["AR-targeted therapies sensitize prostate cancer to cuproptosis by transcriptionally activating\n                    <i>FDX1<\/i>"],"prefix":"10.1073","volume":"123","author":[{"given":"Xuehui","family":"Li","sequence":"first","affiliation":[{"name":"The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]},{"name":"Department of Nephrology, Shanghai TCM-Integrated Hospital affiliated with Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siliang","family":"Wang","sequence":"additional","affiliation":[{"name":"The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Urology, Shuang Hospital, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang","family":"Xie","sequence":"additional","affiliation":[{"name":"The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, 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