Elevated copper concentrations in PCa cell tissues are a hallmark of patients with PCa (46), as demonstrated using in vitro cell line studies (47-49) and a xenograft mouse model (49,50). Notably, patients with PCa exhibit higher than expected serum copper levels (51-53) and elevated serum copper levels may be associated with a poor prognosis in patients with PCa (54). The RNA interference-mediated knockdown of CTR1 decreased copper ion absorption in PCa cells, resulting in the substantial inhibition of tumor growth (50). Collectively, these findings highlighted the role that increased copper ion concentrations may play in sustaining the biological processes of PCa cells, while diminished copper ion levels may fail to support the physiological functions of tumor cells.

Results of a previous study (31) reveal that the expression levels of CRGs in several types of tumor were markedly associated with patient prognosis, indicating that cuproptosis may play a key role in tumor biology and therapeutic response. Results of previous studies (51,55-60) indicate that individuals with malignant tumors, including PCa, exhibit markedly altered levels of Cu in both serum and tumor tissues. Moreover, CRGs play a role in PCa through predicting prognosis, modulating the tumor microenvironment and affecting therapeutic response (54). A range of CRGs may affect the progression of PCa, with CRGs and corresponding functions associated with cuproptosis detailed in Table I. At present, research is focused on the potential of cuproptosis in preventing tumor growth. Consequently, the manipulation of cuproptosis or CRGs has emerged as a viable anti-cancer therapy.

Mitochondrial dysfunction is pivotal for cuproptosis, resulting in oxidative damage to the mitochondrial membrane and compromised enzyme performance in the TCA cycle (29). By contrast, excessive copper accumulation in cellular mitochondria initiates cuproptosis (68), producing substantial amounts of ROS. During PCa progression, ROS levels are increased in PCa cells (69), resulting in DNA mutations, oncogene activation and tumor suppressor gene inactivation. This cascade facilitates malignant cell transformation and the activation of stress-responsive survival pathways, thereby exacerbating the aberrant proliferation of PCa cells (70). In addition, the process of cuproptosis generates ROS, further advancing PCa progression (71). Notably, a requisite level of ROS is essential for tumor cell growth and DNA mutation; however, severe oxidative stress may deplete the capabilities of the antioxidant system, resulting in apoptosis (72). In cuproptosis, ROS are continuously generated, leading to toxic concentrations in PCa cells and notable effects on tumor growth. Results of previous studies (73-75) indicate that the excessive creation and accumulation of ROS are employed to impede PCa progression. Moreover, soy isoflavones, such as genistein and soy glycosides, may elevate copper concentrations in PCa cells through mobilizing endogenous copper and disrupting the expression of copper transporter protein genes, CTR1 and ATP7A, in cancer cells. This process subsequently induced high levels of ROS production, ultimately resulting in apoptosis in PCa cells (76). Moreover, curcumin analogs (77) and felicidin (78) exhibit analogous mechanisms of action to impede PCa cell proliferation. Results of a previous study (79) reveal that alterations in the ATP7B gene inhibits the regulation of copper ion distribution in vivo, resulting in increased copper levels in PCa cells. Similarly, ATP7B protein levels were markedly enhanced in docetaxel-resistant PCa cell lines, resulting in diminished intracellular copper levels. Notably, these levels may be promoted through silencing ATP7B expression or using a combination of disulfiram and copper to enhance intracellular copper concentrations (80). This modified intra- and extracellular copper distribution results in a substantial inhibitory effect on PCa growth, which may be associated with the excessive production of ROS due to copper ion carriers entering PCa cells, as well as antioxidant deficiencies present in these cells (79). Results of a previous study (81) highlight a reciprocal interaction between cuproptosis and copper-induced oxidative stress. The accumulation of ROS may facilitate the progression of PCa and exert an inhibitory effect on it. Cuproptosis may induce excessive ROS production to promote tumor cell death; however, investigations surrounding this dual mechanism are limited (Fig. 2). The specific impact of cuproptosis on PCa requires further validation through relevant experiments to elucidate the mechanism underlying cuproptosis in the context of PCa development.

Copper participates in tumor metabolism and promotes tumor progression. Notably, copper is associated with the progression and spread of PCa (82,83) and it also facilitates tumor angiogenesis (37,38). Angiogenesis markedly contributes to the progression and metastasis of PCa (84), primarily driven by angiogenic factors, including vascular endothelial growth factor, fibroblast growth factor, hypoxia-inducible factor (HIF) and interleukin (85). Results of a previous study (79) reveal that a reduction in copper levels diminishes HIF activity and obstructed tumor angiogenesis. Moreover, restrictions in angiogenesis may limit PCa progression (86). Copper chelators may also diminish intracellular copper ion concentrations and lower copper bioavailability, thereby reducing copper-induced angiogenesis (42). Therefore, lowering copper concentrations to impede tumor angiogenesis may mitigate tumor advancement.

Complexities in lipid metabolism may contribute to carcinogenesis and disease progression. Results of a previous study (87) reveal that disturbances in lipid metabolism are associated with disease advancement and the development of castration-resistant prostate cancer (CRPC). In addition, cholesteryl esters (CE) are excessively accumulated in high-grade PCa and metastatic sites (88). The Wnt/β-catenin signaling pathway plays an important role in the metastasis of PCa and the depletion of CE markedly obstructs Wnt3a secretion through reducing unsaturated fatty acid levels, which inhibit the activation of the Wnt/β-catenin signaling pathway and restrict the acylation of Wnt3a, thereby inhibiting the metastasis of PCa (89). Copper ions also activate the Wnt/β-catenin signaling pathway, resulting in augmented cancer stem cell characteristics and increased resistance to numerous therapies (90). Elevated serum copper levels may be associated with increased serum total cholesterol and HDL cholesterol levels, as well as a heightened risk of dyslipidemia characterized by high serum total cholesterol and LDL cholesterol (91). Results of previous studies (92,93) reveal that zebrafish and grass carp exhibit elevated copper concentrations in their livers when subjected to excess copper, resulting in increased lipid accumulation and levels of triglycerides. These findings indicate that alterations in copper levels, particularly in excess, may influence the progression of PCa by affecting lipid metabolism and signaling system activity; however, further molecular or animal studies are required to validate these mechanisms.

In conclusion, the mechanisms underlying cuproptosis in PCa primarily encompass oxidative stress, intracellular copper distribution, angiogenesis and lipid metabolism dysregulation. Further investigations into these mechanisms may facilitate a deeper comprehension of cuproptosis in PCa and aid in identifying potential therapeutic targets.

Elesclomol (ES) is a copper ion transporter that facilitates the entry of copper ions into cells, often targeting mitochondria. The entry of copper into cells leads to the accumulation of ROS, consequently impeding tumor growth. In cancer therapy, ES may leverage its capacity to produce cuproptosis to eliminate malignant cells. Disulfiram (DSF) functions as a copper ion transporter through binding to copper ions and facilitating entry into the cell. Notably, DSF has previously been investigated for the treatment of specific types of cancer, particularly those with elevated levels of lipoylated proteins (94). The two aforementioned copper ion carriers have been extensively researched for their ability to carry Cu²⁺ into cells or mitochondria to facilitate copper-dependent cell death (Fig. 3). Copper exerts a multifaceted impact on PCa growth and proliferation; however, results of in vitro studies (61,62) consistently demonstrate that ES diminishes PCa cell viability via a reduction in FDX1 expression levels. Moreover, ES promotes keratin formation in tumor cells, inhibits autophagy in PCa via the DLAT/mammalian target of rapamycin pathway and enhances sensitivity to docetaxel and paclitaxel chemotherapy (95). In addition, DSF compounds combined with copper have demonstrated efficacy in breast cancer treatment through downregulating the expression of the phosphatase and tensin homolog (PTEN) associated with human chromosome 10 deletion and activating protein kinase B (AKT) signaling. This indicates a potential for combination therapy utilizing phosphatidylinositol 3-kinase (PI3K)/AKT inhibitors (96). Results of further previous studies (97,98) reveal that PCa may involve the same PTEN and PI3K/AKT signaling pathways for targeted therapy, highlighting that these pathways may inhibit PCa progression. However, previous investigations focused on the role of PTEN and PI3K/AKT signaling pathways in PCa progression remain limited.

Moreover, ES may exhibit potential in the treatment of PCa. Results of a previous study (99) revealed that DSF may inhibit the proliferation of PCa cell lines and this mechanism may be mediated by other pharmacological agents or specific sensitizers, such as copper (100). Thus, copper may be used to suppress the growth of PCa cells (49,101), ultimately improving the survival rate of patients (80).

Collectively, these results revealed that although copper ion carrier-induced cell death is a key form of cell death, few studies have confirmed the efficacy in PCa using in vitro investigations. Results of previous research demonstrated that several substances may elevate intracellular copper ion concentrations, including the aforementioned copper ion carriers, copper ion compounds and several copper chelators that inhibit the increase in copper ion levels. Triethylenetetramine dihydrochloride (102), 8-hydroxyquinoline (103), penicillamine (104), methanobactin (105), Bathocuproine disulphonate (106) and choline tetrathiomolybdate (107) are key compounds that regulate intracellular copper ion concentrations, thereby facilitating or obstructing copper ion-associated biological functions. The aforementioned drugs are theoretically capable of stimulating cell proliferation; however, no previous investigations have been undertaken regarding cuproptosis in PCa. Preliminary experiments should be performed to substantiate this hypothesis and to aid in the development of novel cuproptosis-associated therapies.

A reduction in glutathione (GSH), a natural chelator of intracellular copper ions, results in an elevation of intracellular copper concentration, ultimately culminating in cell death (9). In healthy prostate cells, GSH neutralizes ROS produced by increased copper ion levels from copper ion carriers; thus, providing an antioxidant effect and reducing sensitivity to ROS. Conversely, PCa cells possess diminished levels of GSH and are deficient in antioxidants, rendering them susceptible to ROS generated by copper ion carriers. Subsequently, this may result in PCa cell mortality (79). In addition, elevated copper concentrations facilitate tumor angiogenesis and disrupt lipid metabolism. Steroid-based compounds impede PCa progression through the inhibition of CTR, thereby decreasing copper absorption by PCa cells and mitigating the proliferative effects of copper. These results indicate that the aforementioned compounds may represent innovative anticancer agents targeting anti-copper therapy (35). Results of a further study (108) reveal that the pro-drug, gamma-glutamyl transferase-activated prochelator releasing dithiocarbamate (GGTDTC), is activated by gamma-glutamyl transferase (GGT) in PCa cells. The release of dithiocarbamate (DTC), which chelates with copper ions to form a Cu-DTC complex, is highly toxic and promotes PCa cell death by triggering oxidative stress to generate large amounts of ROS. Ultimately, this interferes with protein ubiquitination. In PCa cells, GGT is often overexpressed and the concentration of copper ions is high. In addition, GGT exhibits a decreased antioxidant capacity, leading to metabolic disorders. This compound is more selective to cancer cells and therefore less toxic to non-tumor cells. In addition, GGT exhibits improved selectivity (108). Thus, the use of copper chelators, in addition to elevated copper ion concentrations that mediate cuproptosis and impede tumor advancement, may diminish intracellular copper levels and initiate cuproptosis. These compounds may be used to leverage the highly toxic characteristics of copper-chelator complexes, which may further inhibit tumor progression to some degree. However, the specific mechanisms remain to be fully elucidated.

Nanotechnology facilitates the targeted delivery of copper ions to tumor sites via modifying responsive groups that coordinate with copper compounds. This process enhances the concentration of copper ions within tumor cells, leading to the toxic oligomerization of lipoylated proteins and the degradation of Fe-S cluster proteins. This ultimately induces cuproptosis in tumor cells and produces a therapeutic effect against cancer (109). Researchers presented a novel nanoparticle, DCM@GDY-CuMOF@DOX, capable of releasing Cu⁺ in the presence of GSH, ultimately facilitating the onset of cuproptosis (110). Concurrently, doxorubicin (DOX) generates high levels of hydrogen peroxide (H₂O₂), which, when catalyzed by Cu⁺, is transformed into cytotoxic ROS via a Fenton-like reaction. Notably, this process induces cancer cell death. ROS produced via this method may trigger apoptosis, resulting in oxidative DNA damage and mitochondrial impairment. By contrast to the administration of DOX alone, nanoparticles enveloped within the PCa cell membranes (DU145 cell membrane; DCM) exhibit isotypic targeting capabilities, allowing them to specifically identify and target identical PCa cells. This process may diminish the likelihood of non-specific targeting during blood circulation. The non-specific adsorption and elimination in the bloodstream extend circulation time within the body, thereby minimizing toxicity to healthy tissues and enhancing the precision of targeting PCa cells for treatment. Haemolysis experiments, histopathological assessments and serum biochemical analyses demonstrated that nanoparticles did not induce notable damage to healthy cells and tissues; however, they did exhibit targeting capabilities and biocompatibility. Thus, these may exhibit potential in clinical practice (110). Results of a previous study (111) demonstrate that cuprous oxide nanoparticles (CONPs) selectively inhibited the proliferation of CRPC cells. Toxicological investigations revealed that CONPs elevate copper demand and uptake capacity and induce cell cycle arrest and apoptosis in cancer cells. In addition, CONPs suppressed stem cell properties and the Wnt signaling pathway and exhibited minimal effects on healthy prostate epithelial cells. Moreover, Cu(DDC)₂ nanoparticles facilitate the transport of Cu²⁺ into cells, elevate intracellular copper levels and mediate the apoptosis of paclitaxel-resistant PCa cells (112). These nanoparticles facilitated tumor site-specific accumulation and induce cuproptosis through loading copper ions and employing a responsive release mechanism, offering a novel, targeted and biocompatible therapeutic alternative for PCa treatment.

Moreover, liposomal copper (LpCu) effectively transports copper ions into PCa cells via encapsulating copper salts within liposomes. PCa cells treated with LpCu exhibit metabolic toxicity comparable with that of free copper salts, indicated by increased intracellular copper levels and increased levels of ROS, apoptosis and necrosis (113). Specific steroid-based compounds form complexes with copper ions, diminishing the concentration of free copper ions within the cell. Thus, the influx of copper ions into PCa cells via CTR1 is reduced, effectively impeding copper absorption by PCa cells and disrupting their biosynthesis to inhibit PCa cell proliferation (35).

Surgery remains the primary treatment option for localized PCa and androgen deprivation therapy is effective for patients with biochemically recurrent and metastatic hormone-sensitive PCa. However, resistance and progression to CRPC may still occur, along with suboptimal therapeutic outcomes following chemotherapy and immunotherapy (54). At present, research is focused on the role of cuproptosis in malignancies, to determine the effects on cell growth and the specific underlying mechanisms.

Cuproptosis affects treatment resistance and contributes to the management of PCa. Notably, enzalutamide augments the susceptibility of CRPC cells to copper ion carriers and improves treatment efficacy through facilitating copper-dependent cell death. This combination therapy efficiently suppresses the proliferation of CRPC cells and reverses the resistance of enzalutamide-resistant cells both in vitro and in vivo (43). By contrast, enzalutamide-resistant PCa cells demonstrate high levels of resistance to cuproptosis and the alteration of NUDT21 activity or the addition of PDHA improve the effectiveness of the copper ionophore, potentially leading to treatment resistance in PCa (67). Results of a further previous study revealed that a combination of disulfiram and copper led to a notable reduction in the expression of ATP7B and the elevation of intracellular copper levels in PCa cell lines, rendering resistant cells sensitive to the growth-inhibitory and apoptotic effects of docetaxel (80). Results of both in vivo and in vitro studies demonstrate that a combination of DSF and copper markedly reduces cell proliferation and the induction of apoptosis, indicative of the increased antitumor efficacy of docetaxel (80). Moreover, DSF and copper directly interact with ATP7B, leading to the downregulation of its downstream proteins, including copper metabolism MURR1 Domain containing 1, α-clusterin and S-phase kinase associated protein 2. Simultaneously, DSF and copper promote upregulation of cyclin-dependent kinase inhibitor 1 thus inhibiting tumor growth (80). Results of a previous study (95) reveal that a combination of ES and CuCl₂ (ES-Cu) effectively induces copper-mediated cytotoxicity in PCa cells, inhibits autophagy via DLAT upregulation and subsequently promotes cell retention in the G₂/M phase, thereby augmenting the chemotherapeutic efficacy of docetaxel. In vivo experiments further demonstrate that the combination of ES-Cu and docetaxel markedly suppresses tumor growth in a PCa transplantation model using nude mice, where tumor proliferation was markedly inhibited (95). Collectively, these data indicated that copper-induced cell death may impact the sensitivity of PCa to pharmacological agents.

Complanatoside A (CA) is a flavonoid derived from the Traditional Chinese Medicine, Semen Astragali Complanati. Results of a previous study (114) reveal that CA downregulates the expression of the copper efflux-associated protein, ATOX1, promotes the accumulation of intracellular copper ions, inhibits mitochondrial activity and induces copper-mediated cell death. Notably, this agent markedly suppresses the proliferation, invasion and growth of PCa cells both in vivo and ex vivo, with no notable damage to major organs in experimental animal models (114). Nuclear factor-activated T cell 5 (NFAT5) is a transcription factor that activates T cells and plays a key role in cellular stress response, immunological response and cell proliferation. Results of previous study revealed that NFAT5 acts as a target gene of microRNA (miR)-206 through bioinformatics analysis and database predictions. In addition, results of a previous study (115) reveal that the long-chain non-coding RNA (lncRNA), AP000842.3, acts as a target gene of miR-206, functioning as a competitive endogenous RNA (ceRNA) that modulates the expression levels of NFAT5. Thus, this lncRNA affects the sensitivity of PCa cells to copper death inducers. In cellular experiments, NFAT5 knockdown markedly increases the sensitivity of PCa cells to copper-induced cytotoxicity and this was highlighted by elevated intracellular copper ion concentrations and reduced ROS levels (115). Therefore, the interaction of lncRNA AP000842.3 with miR-206 may play a key role in regulating NFAT5 expression. Notably, this regulatory mechanism may be partly dependent on miR-206, providing a novel potential target for PCa diagnosis and treatment (115).

Resveratrol, a polyphenol compound mainly located in red grapes and pomegranates, is an antioxidant that inhibits PCa cells through interacting with copper ions. This process contributes to the redox of copper ions and the generation of ROS, leading to an increase in intracellular oxidative stress and interference with intracellular signaling pathways, such as MAPK, PI3K/Akt and NF-κB pathways. Moreover, results of a this study (116) reveal that resveratrol inhibits cell cycle progression, thus inhibiting PCa cell proliferation. This compound also activates key intracellular apoptotic signaling pathways, such as the mitochondrial pathway and death receptor pathway, to promote the apoptosis of PCa cells. By contrast, copper ion chelation reverses the anticancer effects of resveratrol, further confirming the key role of copper ions in the action of resveratrol. In addition, the observed elevation of copper ions may facilitate their absorption and storage, promoting the harmful effects of resveratrol through the upregulation of the copper transporter protein, CTR (116). Collectively, results of these investigations indicated that copper and copper-induced cytotoxicity may serve as viable therapeutic approaches for the treatment of PCa.

Despite the limited number of studies on cuproptosis in PCa, previous studies revealed that CRGs may act as novel therapeutic targets, playing a key role in the progression of PCa (Table II). Moreover, cuproptosis may be associated with key predictors of PCa, exhibiting potential as a novel indicator of the prognosis of patients with PCa and their responsiveness to treatment (Table III).

Irrespective of the trajectory of predictive modeling, research is focused on the development of novel molecular instruments for prognostic evaluation and clinical decision-making in PCa. Cuproptosis-based prognostic models exhibit efficacy in predicting outcomes of patients with PCa; however, the recurrence prediction mediated by CDI surpasses that of the cuproptosis-based prognostic models (123). CRLs obtained from bioinformatics analysis not only aid in the establishment of a prognostic prediction model for patients with PCa, but also the results of cellular experiments reveal that the knockdown of CRLs, particularly AC106820.5, may inhibit the proliferation, migration and invasive capabilities of PCa cells (127). Collectively, these data illustrate that bioinformatics analyses may be used to identify potential therapeutic targets in the treatment of PCa. Notably, the aforementioned models may also be used to predict responsiveness to immunotherapy, leading to the development of personalized treatment options that improve patient outcomes and quality of life.