The CP-STPG3-AS1 axis regulates lipoylation and cuproptosis in castration-resistant prostate cancer

Background Prostate cancer (PCa), particularly metastatic castration-resistant PCa (mCRPC), remains therapeutically challenging. Cuproptosis, a copper-dependent cell death driven by lipoylated tricarboxylic acid cycle proteins, is implicated in PCa progression, but whether ceruloplasmin (CP), a key copper-binding glycoprotein, modulates cuproptosis in PCa and the underlying mediators remain unknown. Methods We integrated bioinformatic analysis of TCGA-PRAD data (550 PCa, 52 normal tissues) with in vitro validation in two androgen-independent CRPC cell lines: PC-3 cells received exogenous CP gradients, while 22Rv1 cells underwent CP knockdown and rescue experiments with qPCR, Western blot, MitoSOX flow cytometry, and CCK-8 assays. Results Eighty CP-cuproptosis intersection genes were identified. Cuproptosis core genes (FDX1, DLST, LIAS, DLD) were significantly upregulated in PCa (all p<0.001), while CP showed no differential expression but weak positive correlations with these genes (r=0.205-0.300). Exogenous CP concentration-dependently reduced PC-3 metabolic activity and induced apoptosis-related morphology. In 22Rv1 cells, CP knockdown downregulated lncRNA STPG3-AS1, upregulated cuproptosis-related markers (FDX1, DLAT, lipoylated proteins) and mitochondrial ROS, and inhibited proliferation; STPG3-AS1 overexpression reversed all these effects. No gene showed independent prognostic value. Conclusion STPG3-AS1 mediates CP-regulated lipoylation and cuproptosis-associated molecular changes in CRPC cells, identifying a novel CP-STPG3-AS1-cuproptosis regulatory axis with therapeutic potential for advanced prostate cancer.