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Although serum copper is elevated in patients with prostate cancer, whether this is sufficient to trigger physiological cuproptosis remains unclear. Here, we show that tumor copper levels positively correlate with androgen receptor (AR) activity, and castration\u2010resistant prostate cancer (CRPC) with hyperactivated AR exhibits pathological copper accumulation. AR activation enhances copper uptake while simultaneously conferring tolerance to copper toxicity, creating a buffered copper state. This adaptive response is mediated by metal\u2010responsive transcription factor 1 (MTF1), which is transcriptionally upregulated by AR and undergoes EP300\u2010dependent lactylation of lysine 218, promoting copper\u2010induced nuclear translocation. Nuclear MTF1 activates metallothioneins (MT1E, MT1F, and MT1M) that sequester cytosolic copper and restrict mitochondrial copper accumulation. Disrupting MTF1 collapses this buffering system, enabling endogenous copper to trigger cuproptosis and suppress CRPC growth. These findings identify cuproptosis as a therapeutically exploitable vulnerability in CRPC.<\/jats:p>","DOI":"10.1002\/advs.77110","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:50:55Z","timestamp":1786467055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EP300\u2010Mediated MTF1\u2010K218 Lactylation Buffers AR\u2010Driven Copper Overload to Suppress Cuproptosis in Castration\u2010Resistant Prostate Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1658-750X","authenticated-orcid":false,"given":"Kai","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology Jiangsu Key Laboratory of Urological Disease Prevention and Treatment The Second Affiliated Hospital of Nanjing Medical University Nanjing Medical University  Nanjing 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