EP300‐Mediated MTF1‐K218 Lactylation Buffers AR‐Driven Copper Overload to Suppress Cuproptosis in Castration‐Resistant Prostate Cancer

Inducing cuproptosis for cancer therapy currently relies on supraphysiological copper or copper ionophores. 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‐resistant 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‐responsive transcription factor 1 (MTF1), which is transcriptionally upregulated by AR and undergoes EP300‐dependent lactylation of lysine 218, promoting copper‐induced 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.