Cuproptosis in prostate cancer: Molecular mechanisms, prognostic biomarkers and therapeutic frontiers of cuproptosis‑related genes (Review)

Abstract

Prostate cancer (PCa) is among the most prevalent malignancies in males globally and management remains complex. In recent years, cuproptosis, an emerging form of cell death, has offered novel insights for PCa treatment. Cuproptosis refers to a copper‑mediated cellular death mechanism that is intricately associated with mitochondrial metabolism, with cuproptosis‑related genes (CRGs) exerting a notable effect on both cuproptosis and PCa. CRGs and other cuproptosis‑associated indicators have demonstrated efficacy as prognostic predictors of PCa and these predictors may exhibit potential as novel therapeutic targets in the treatment of PCa. The mechanisms underlying cuproptosis in PCa remain to be fully elucidated; thus, further research is required to validate the expression patterns of CRGs and their associated indicators and examine the potential association with the characteristics, treatment responses and prognoses of patients with PCa. The present study aimed to investigate novel therapeutic strategies that may enhance the prognosis and quality of life of patients with PCa.

Keywords: cell death; copper metabolism; cuproptosis; cuproptosis‑related genes; prostate cancer.

Figure 1

Processes of copper metabolism and cuproptosis. Cu²⁺ are reduced to Cu⁺ by STEAP/DCYTB in the gut epithelium and transported into cells via CTR1. Inside target cells, Cu⁺ interferes with Fe-S clusters, generates ROS and leads to mitochondrial dysfunction. Excess Cu⁺ induces protein aggregation via lipoylated proteins, mediated by FDX1 and LIAS, ultimately causing cuproptosis. STEAP, prostate six transmembrane epithelial antigen; DCYTB, duodenal cytochrome b; CTR1, copper transporter 1; TCA, tricarboxylic acid cycle; Fe-S, iron-sulfur; ROS, reactive oxygen species; FDX1, ferredoxin 1; DLAT, dihydrolipoamide S-acetyltransferase; LIAS, lipoic acid synthetase.

Figure 2

Dual mechanisms underlying copper and cuproptosis in PCa. Mitochondrial dysfunction is central to cuproptosis, leading to oxidative damage and inhibition of the TCA cycle. Excess copper accumulation in mitochondria triggers cuproptosis and sustained ROS production. Moderate ROS levels promote DNA mutations and oncogenic signaling, driving tumor progression. In contrast, excessive ROS overwhelm antioxidant defenses and induce tumor cell death. The specific involvement in PCa requires further validation. PCa, prostate cancer; TCA, tricarboxylic acid cycle; ROS, reactive oxygen species.

Figure 3

Mechanism of copper ion carriers. Elesclomol and disulfiram enhance intracellular Cu⁺ accumulation in tumor cells. In the presence of elevated lipoylated proteins or ALDH expression (such as PCa), Cu⁺ induces toxic stress within mitochondria, triggering cuproptosis and resulting in tumor cell death. ALDH, acetaldehyde dehydrogenase; PCa, prostate cancer.