Cuproptosis and prostate cancer: from molecular mechanisms and microenvironment remodeling to precision therapy

Prostate cancer (PCa) is a leading malignancy, and progression to castration-resistant prostate cancer (CRPC) remains a central therapeutic challenge. Cuproptosis, a copper-dependent cell death mechanism first characterized in 2022, is triggered by copper binding to lipoylated tricarboxylic acid (TCA)-cycle proteins, inducing their aggregation, Fe-S cluster protein instability, and mitochondrial proteotoxic stress. This review critically evaluates the emerging but still heterogeneous evidence linking cuproptosis to PCa, explicitly distinguishing prostate cancer-specific data from pan-cancer,non-prostate, bioinformatic, and preclinical observations. We describe the core machinery, including ferredoxin 1 (FDX1), dihydrolipoamide acetyltransferase (DLAT), protein lipoylation enzymes, and copper transport/chaperone systems, while emphasizing differences from apoptosis and ferroptosis. In PCa, altered copper homeostasis and mitochondrial metabolic rewiring provide a biologically plausible vulnerability, but current evidence does not yet establish cuproptosis as a validated clinical driver or therapeutic target. We therefore summarize cuproptosis-related gene expression profiles and prognostic models as hypothesis-generating biomarkers, and provide a prostate cancer-specific evidence table that separates bioinformatic, in vitro, in vivo, and clinical levels of support. We also review potential links with metabolic reprogramming, immune microenvironment modulation, PD-L1 regulation, androgen receptor signaling, PTEN/PI3K pathway activity, epigenetic regulation, and crosstalk with ferroptosis. Therapeutically, copper ionophores such as elesclomol and disulfiram/copper, and copper-depleting approaches such as chelators, are discussed as investigational strategies rather than near-clinical solutions. Particular attention is given to toxicity, narrow therapeutic windows, negative or inconclusive clinical data, the absence of validated companion diagnostics in PCa, and the need for patient-selection biomarkers based on copper handling, FDX1/lipoylation status, and mitochondrial dependency. Finally, we outline the experimental and translational studies required before cuproptosis-directed interventions can be rationally tested in advanced PCa.