Research progress on the regulation of cuproptosis-related genes by non-coding RNAs in tumors
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Yuxin Du
Abstract
Cuproptosis represents a mechanistically distinct programmed cell death pathway divergent from canonical apoptosis, necrosis, and ferroptosis. This copper-dependent process critically modulates tumorigenesis, malignant progression, and clinical outcomes in neoplastic diseases. Non-coding RNAs (ncRNAs) modulate the expression of cuproptosis-related genes (CRGs) in tumors through the competing endogenous RNA mechanism. This regulation leads to copper ion accumulation, oxidative stress response, protein lipoylation, and ubiquitin-proteasome system activation, which eventually inhibit the occurrence and progression of tumors. The modulation of CRG expression by ncRNAs offers new perspectives for precision-targeted cancer therapy. This could potentially help develop more accurate and effective treatment approaches. Here, we review the mechanisms underlying cuproptosis, summarize the regulatory roles of ncRNAs in tumors, analyze the expression patterns of CRGs across multiple cancer types and their impact on patient prognosis, and elucidate the molecular mechanisms by which ncRNAs regulate cuproptosis in tumors. Furthermore, we provide clinical perspectives and highlight the potential opportunities for developing innovative therapeutic strategies for cancer.
Introduction
Research background
Cancer is the second leading cause of death worldwide [1], accounting for approximately 9.6 million cancer-related deaths annually, and representing about 17 % of total global mortality [2]. Identifying effective diagnostic and therapeutic targets for cancer is urgently needed. Orchestrating genomically-tailored intervention blueprints, precision medicine propels oncological diagnostics/therapeutics into unprecedented acuity-efficacy dimensions through evolutionary technological currents [3]. Non-coding RNAs (ncRNAs) architect the regulatory scaffold of gene expression, emerging as pivotal molecular engineers in precision oncology [4]. Cancer-associated deregulation profiles of numerous ncRNAs position them as exploitable diagnostic compasses in clinical landscapes [5]. In 2022, researchers unveiled a novel cell death mechanism and named it cuproptosis [6]. Cuproptosis is a form of regulated cell death triggered by copper (Cu), closely linked to mitochondrial metabolism, and critically involved in cancer cell proliferation, invasion, and chemoresistance [7]. ncRNAs are also closely associated with tumors [8]. Reportedly, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) can affect tumorigenesis and progression by regulating the expression of cuproptosis-related genes in tumor cells [9].
Research objectives
This study aims to systematically elucidate the mechanisms of cuproptosis, with a dedicated focus on the regulatory roles of ncRNAs. We will comprehensively integrate and analyze existing research data to thoroughly summarize the differential expression patterns of cuproptosis-related genes across various malignancies and their correlations with patient prognosis. Furthermore, the work seeks to provide detailed summaries of recently identified key ncRNAs involved in regulating tumor cuproptosis and their molecular mechanisms of action, thereby revealing the multi-dimensional interaction networks between ncRNAs and cuproptosis. Collectively, these objectives are designed to outline the molecular mechanisms underlying cuproptosis dysregulation in malignant tumors and establish a gravitational center for precision oncology research orbiting cuproptosis-based paradigms. An overview of the review study is shown in Figure 1.
Overview of the study.
Overview and regulatory mechanisms of cuproptosis
Cuproptosis
Copper ions exhibit a strong redox activity [10]. Intracellular copper accumulation can elicit oxidative stress (OS) [11] and impair normal cell functioning, necessitating stringent regulation of copper homeostasis [12]. Copper homeostasis is intimately linked to disease progression and pathogenesis [13]. In March 2022, Tsvetkov et al. [6] characterized the molecular pathway by which copper induces cell death and named it “cuproptosis”. This discovery marked a landmark in the study of the mechanism of copper-induced cell death. Cuproptosis represents a molecularly unique cell death modality that operates through mechanisms orthogonal to all established programmed cell death pathways [14]. Excess copper ions bind to the acylated components of the mitochondrial tricarboxylic acid cycle, leading to the accumulation of acylated proteins, alterations in mitochondrial respiration, loss of iron-sulfur cluster proteins, activation of endoplasmic reticulum stress responses, and, eventually, cell death.
Copper ions activate OS responses
Copper is a basic transition metal cofactor, with specific redox functions and protein-binding capabilities. It is an important catalytic factor and structural cofactor in various biological processes [15]. Copper metabolism in the body maintains dynamic equilibrium through the regulation of copper homeostasis mechanisms, thereby sustaining normal physiological activities. When the internal environment of the body is disrupted, it can lead to the dysregulation of copper metabolism within cells [16]. Excess copper is considered to be an effective oxidant that increases reactive oxygen species (ROS) production and promotes OS [17]. OS initiates when ROS production exceeds the threshold of compensatory antioxidant responses [18]. Physiological ROS concentrations function as crucial signaling mediators for cellular homeostasis, whereas supraphysiological accumulation induces protein and lipid peroxidation, genotoxic stress, and irreversible commitment to regulated cell death pathways [19].
Copper ions induce protein acylation
Ferredoxin 1 (FDX1) as an essential reductase, converts ionophore-delivered Cu(II) to toxic Cu(I) within mitochondria [20]. Simultaneously, under the influence of FDX1, lipoyl synthase (LIAS) connects the thioacetyl moiety to dihydrolipoamide S-acetyltransferase (DLAT), one of the components of pyruvate dehydrogenase [21]. Simultaneously, FDX1 regulates DLAT binding to copper. Cu(I) binds to lipoylated mitochondrial proteins, particularly DLAT, instigating its aggregation and triggering proteotoxic stress and ultimately cell death [22].
Copper ions interfere with the ubiquitin-proteasome system (UPS)
As the primary protein hydrolysis system responsible for controlling protein degradation, UPS regulates various cellular processes in eukaryotic cells, such as DNA repair, stress response, and cell proliferation [23]. Ubiquitination proceeds through an E1-E2-E3 enzymatic cascade: E1 harnesses ATP hydrolysis to drive ubiquitin adenylation coupled with thioester tethering at its catalytic cysteine, activated ubiquitin is then transferred to the E2 conjugating enzyme, E2-E3 complex cooperatively catalyzes isopeptide linkage between the C-terminal glycine of ubiquitin and lysine residues of substrate proteins, thereby establishing substrate-specific ubiquitination [24]. Beyond inducing oxidative stress, copper complexes can also act as potential inhibitors of the UPS. Representative compounds (e.g., CuET, Hinokitiol-Cu) were found to inhibit core components of the UPS mechanism, including the 20S proteasome, 19S proteasome-associated deubiquitinase, and the NPLOC4/NPL4 complex [25]. Chelation-enhanced potency enables copper ions to significantly amplify UPS inhibitors’ efficacy [26]. These findings collectively highlight the disruptive role of copper ions in the UPS.
The mechanism underlying cuproptosis is depicted schematically in Figure 2.
Mechanism of cuproptosis. Elesclomol shuttles Cu2+ into the mitochondrial matrix, leading to the accumulation of copper. FDX1 reduces Cu2+ to Cu+, resulting in the formation of ROS and potentially destabilizing Fe-S cluster proteins. Additionally, FDX1 interacts with LIAS, promoting the lipoylation of DLAT. Cu+ can directly bind to the lipoyl groups of lipoylated DLAT through disulfide bonds, further inducing DLAT oligomerization. Cu+ can also inhibit the UPS. These multiple molecular mechanisms collectively lead to copper-dependent cell death.
Overview of ncRNAs
ncRNAs represent a class of evolutionarily conserved transcripts. They can perform important biological functions in cells through various mechanisms [27], and their dysregulation has been implicated in disease [28]. As molecular switches in cancer, ncRNAs functionally pivot between igniting oncogenesis and deploying tumor suppression to dictate disease outcomes [8].
MiRNAs
MiRNAs, which are small ncRNAs about 22 nucleotides in length that regulate the expression of other RNAs, particularly mRNAs, by binding at the 5′ end of the miRNA to complementary sequences in the target RNA. Altered miRNA expression has been observed in all cancer types studied [29]. Aberrant miRNA expression constitutes a hallmark of cancer development [30]. Deng et al. [31] demonstrated that miR-192 and miR-215 undergo marked overexpression in gastric adenocarcinoma, functionally enhancing neoplastic proliferation and metastatic propensity. It is reported that dysregulation of specific miRNAs can also be linked to chemoresistance through various mechanisms, including increased drug efflux, alterations in drug targets, abnormal DNA repair pathways, evasion of apoptosis, dysregulation of cell cycle control, and so on [32]. Critically, miRNAs maintain strong stability in living organisms, supporting their reliability in clinical use [33].
LncRNAs
LncRNAs constitute transcripts>200 nucleotides [34]. Distinct lncRNA species orchestrate gene regulatory networks across epigenetic modification, transcriptional machinery assembly, and post-transcriptional processing [35]. Dysregulation of specific lncRNAs further correlates with various diseases, including cancers [36]. For example, MALAT1 overexpression predicts metastasis in lung adenocarcinoma (LUAD) [37]. Cao et al. [38] found that lncRNA-RMRP promotes the progression of bladder cancer through miR-206.
CircRNAs
Defined by their circular configuration, circRNAs arise from either exon circularization via reverse splicing or non-canonical splicing pathways, conferring resistance to exoribonucleolytic degradation. These stable RNA circles have been found to exhibit dysregulated expression patterns across multiple cancer types, implicating their functional significance in both the initiation and development of malignant tumors [39]. For example, Yuan et al. [40] found that the upregulation of circRNA_102231 promotes the progression of gastric cancer.
Therapeutic potential and hurdles of ncRNAs in cancer treatment
Accumulating evidence demonstrates that ncRNAs govern tumoral pathogenesis by reprogramming cuproptosis-associated transcriptional networks, establishing them as therapeutic targets. ncRNA-based mimics and inhibitors – including miR-34a mimic MRX34 (suppressing metastasis/stemness in clinical trials) and antisense oligonucleotides (ASOs) that sequester target mRNAs – demonstrate therapeutic potential [41], 42]. Despite this promise, ncRNA therapeutics face translational barriers: low delivery efficiency, chemical and enzymatic instability, immune evasion, and poor tumor adaptability. Zhou et al. [43] engineered a versatile multimodal nanoplatform leveraging bismuth-sulfide nanoflorets (Bi@PP) for high-precision delivery of miR-339 to overcome stemness and radioresistance in esophageal cancer. Yin et al. [44] developed a miR-nanosponge that can specifically capture multiple miRNAs involved in tumor progression, thereby contributing to meaningful glioblastoma treatment. The emergence of nanoparticle-mediated RNA delivery has unlocked the potential of novel therapeutic approaches in cancer treatment. In addition, gold nanoparticles exhibit exceptional synthetic tunability and surface engineerability, enabling programmable conjugation of therapeutic payloads, targeting moieties, and stabilization ligands. Based on this, the effectiveness of tumor treatment may be improved [45]. Although this paradigm-shifting technology demonstrates compelling preclinical efficacy, its clinical translation remains a challenge.
Cuproptosis-related genes and cancer
Tsvetkov et al. [6] identified 10 key cuproptosis-related genes, including the positive regulators FDX1, dihydrolipoamide dehydrogenase (DLD), DLAT, LIAS, pyruvate dehydrogenase E1 β subunit (PDHB), pyruvate dehydrogenase E1 α subunit (PDHA1), and lipoyltransferase 1 (LIPT1) and the negative regulators metal regulatory transcription factor 1 (MTF1), glutaminase (GLS), and cyclin-dependent kinase inhibitor 2A (CDKN2A).
Positive regulators of cuproptosis in cancer
FDX1
FDX1 is an iron-sulfur protein that is involved in a variety of redox reactions. It can reduce copper ions from the divalent to the monovalent state, thereby exhibiting enhanced cytotoxicity and affecting cellular functions [46]. FDX1 has been identified as a pivotal mediator in cuproptosis regulation. Genetic ablation of FDX1 results in: (1) total elimination of protein lipoylation, (2) impaired mitochondrial oxidative phosphorylation, (3) marked buildup of pyruvate and α-ketoglutarate metabolites, (4) significant reduction in succinate concentration, and (5) destabilization of iron-sulfur cluster-containing proteins [47], 48].
FDX1 is highly expressed in STAD compared to normal tissues in the TCGA STAD dataset. Patients with STAD with a low FDX1 expression had worse overall survival [49]. This suggests that FDX1 may exert a tumor-suppressive role in STAD. Research observed a significant downregulation of FDX1 expression in HCC tissues. High FDX1 expression was linked to longer survival [50]. Consequently, therapeutic strategies directed at modulating FDX1 expression may constitute a viable approach for the treatment of HCC. FDX1 expression was decreased in most patients with COAD, with a minority showing increased expression. COAD patients with high levels of FDX1 expression are more likely to survive [51]. Thus, FDX1 may represent a promising therapeutic vulnerability COAD by orchestrating dual mechanisms of cuproptosis induction and tumor immunomodulation. The transcriptional levels of FDX1 were lower in KIRC than in normal tissues. Kaplan-Meier analysis demonstrated that endothelial cells with attenuated FDX1 expression exhibited reduced infiltration, ultimately correlating with progressive attrition of overall survival [52]. Therefore, selective induction of FDX1-mediated cuproptosis in vascular endothelial cells represents a promising strategy to inhibit metastasis of KIRC. FDX1 was expressed at high levels in glioblastoma, and its expression was positively associated with tumor progression and changes in immune cell infiltration [53]. Synthetically, selectively inducing this FDX1-dependent cuproptosis disrupts carcinogenic signalling pathways and reshapes the immunosuppressive microenvironment, providing a critical therapeutic hub for precision oncology.
LIPT1 and LIAS
LIPT1 and LIAS are essential components in the post-translational modification of proteins with lipoic acid. Lipoic acid serves as a crucial cofactor for mitochondrial enzymes participating in oxidative decarboxylation reactions. The gene products of LIPT1 and LIAS constitute essential components of the lipoylation pathway, facilitating the covalent attachment of lipoic acid to critical metabolic enzymes including PDC that plays vital roles in aldehyde metabolic processes [54].
Higher LIPT1 expression correlates with elevated risk scores in COAD patients. Experimental validation confirms its pro-tumorigenic role in fueling COAD progression [55], positioning LIPT1 as an actionable metabolic node for therapeutic interception. Overexpression of LIPT1 in NSCLC potentiates anti-tumor activity through growth suppression and apoptotic induction. LIPT1 downregulated the copper chaperone for antioxidant 1, thereby hindering NSCLC progression [56]. Therefore, the functional inhibitory effect of LIPT1 on tumors establishes its eligibility as a candidate for a detectable biomarker in the clinical application of NSCLC. Elevated LIPT1 expression is associated with significantly prolonged overall survival in melanoma patients following immunotherapy compared to counterparts with diminished expression [57]. LIPT1’s immunomodulatory role evidenced in melanoma survival extension post-immunotherapy unveils its synergistic potential with immune checkpoint blockade. These findings hold promises for improving clinical management strategies in cancer patients.
Cai et al. [58] indicated that LIAS expression was upregulated in cholangiocarcinoma (CHOL), LIHC, and LUAD, whereas it was downregulated in breast cancer (BRCA), COAD, KIRC, prostate adenocarcinoma (PRAD), rectal adenocarcinoma (READ), thyroid carcinoma (THCA), and uterine corpus endometrial carcinoma (UCEC). LIAS alterations in ESCA portend truncated disease-specific survival (DSS), yet remain decoupled from disease-free survival (DFS), overall survival, or PFS. Elevated LIAS expression heralds improved multi-dimensional survival in breast cancer, encompassing overall survival, distant metastasis-free survival (DMFS), post-progression survival (PPS), and RFS. Lung cancer patients with a high LIAS expression showed poorer overall survival and first progression (FP). Patients with COAD with LIAS gene alterations had worse PFS, but no significant differences were observed in their DFS, DSS, or overall survival. These findings suggest that LIAS functions as a pivotal orchestrator in cancer biological networks, with its dysregulation designating a dual-purpose biomarker for risk-stratified therapeutic guidance and immunoreactivity landscape assessment.
DLAT, DLD, PDHA1, and PDHB
The PDC serves as a critical mitochondrial metabolic checkpoint, directly governing cuproptosis execution [6], 59]. Its prognostic relevance in oncology is increasingly recognized. Structurally, PDC comprises: pyruvate dehydrogenase/decarboxylase (E1/PDH), E2/DLAT, and E3/DLD [60]. DLAT forms the E2 component of the PDC [61]. DLD contributes to the formation of the E3 component of the PDC [62]. PDHA1/PDHB heterotetramer form pyruvate dehydrogenase to catalyze pyruvate decarboxylation [63].
Comparative transcriptomics revealed DLAT expression was significantly lower in normal brain tissue samples than in LGG. Furthermore, DLAT is a predictor of poor overall survival and DSS in patients with LGG [64]. Compared to that in normal tissue, DLAT is lowly expressed in HER2-positive breast cancer patients. High expression of DLAT was linked to resistance to HER2-targeted therapy and sensitivity to immunotherapy [65]. Ding et al. [49] found that accentuated DLAT expression in STAD relative to gastric epithelia portended accelerated mortality. These results suggest that DLAT has important prognostic value in STAD. DLAT is abundant in normal tissues, its levels are markedly decreased in ccRCC. This loss of DLAT is associated with poorer patient survival. Therefore, DLAT may act as a tumor-suppressing factor in ccRCC [66]. In summary, DLAT, as a tumor biological modulator, has contributed to the development of precision oncology.
DLD was significantly overexpressed in STAD. Cell assays confirmed the expression of DLD in gastric cancer cell lines, revealing that DLD expression was significantly higher in gastric cancer cell lines than in gastric epithelial cells [67]. The pathologically dysregulated DLD expression signature across gastric carcinogenesis unveils potential targets for treatment. The expression of DLD was significantly elevated in breast cancer tissues compared with neighboring tissues. In vitro experiments showed that downregulation of DLD significantly inhibited breast cancer cell progression [68]. Therefore, DLD emerges as a promising diagnostic and prognostic marker, establishing actionable nodes to treat cancer while leveraging its immunometabolic nexus to potentiate checkpoint blockade efficacy. Li et al. [69] discovered that DLD was expressed at high levels in LUAD tissues, and a high DLD expression level was significantly linked with shorter overall survival. Synthetically, DLD expression manifests prognostic relevance in heterogeneous cancer types while functioning as a biological executor governing the oncogenic triad: tumorigenic initiation, metabolic reprogramming, and immune niche sculpting.
As a key subunit of the PDC, PDHA1, which comprises two α and two β subunits, plays a critical role by acting as a gatekeeper enzyme between glycolysis and the mitochondrial citric acid cycle [70]. PDHA1 can promote the invasion, proliferation, and lymphatic metastasis of NB cells through the cell cycle pathway [71]. The correlation between PDHA1 expression and tumor staging and NB cell infiltration can be used to develop personalised immunotherapy techniques for these patients. The PDHA1 expression levels were higher in normal breast tissues than in breast cancer tissues. PDHA1 upregulation is connected to shorter overall survival and poorer RFS outcomes in breast cancer patients [72]. Therefore, PDHA1 is effective in predicting the prognosis of breast cancer. High PDHA1 expression was connected to shorter overall survival and PPS in the TCGA STAD database, indicating poor prognosis [73]. Sun et al. [74] found that high expression of PDHA1 inhibited the Warburg effect and promoted apoptosis in HCC through a mitochondrial pathway. Furthermore, research indicates that low PDHA1 expression was significantly linked to high overall survival in HCC patients [75]. Based on this, we believe that PDHA1 operates as a metabolic rheostat in HCC. Elevated PDHA1 expression in ovarian tumors was closely associated with improved patient outcomes [76]. Thus, reduced PDHA1 expression may be associated with tumor progression. In summary, PDHA1 may be closely associated with tumor metabolism.
PDHB, a nuclear-encoded component of the pyruvate dehydrogenase complex (PDC) and recognized cuproptosis modulator, catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. This subunit constitutes an essential structural and functional element within the PDC [77]. Rong et al. [78] revealed that PDHB expression was downregulated in most cancers, including colon adenocarcinoma, esophageal carcinoma, and rectal adenocarcinoma, whereas it was highly expressed in HCC. PDHB mRNA and protein were lowly expressed in ccRCC tissues compared to normal tissues. High expression levels of PDHB were related to better survival outcomes. Therefore, PDHB emerges as a metabolically cognizant diagnostic architect, delineating actionable vulnerabilities for combinatorial immuno-targeted therapeutic paradigms.
Negative regulators of cuproptosis in cancer
MTF1
MTF1 is a key transcription factor. It specifically recognizes and binds to target DNA sequences, known as metal-response elements, through its zinc finger domain, thereby initiating the transcription of downstream genes [79]. MTF1 activates the transcription of the copper-binding protein metallothionein (MT) by binding to metal-responsive elements in the MT promoter [80].
To investigate the expression of MTF1, Zhang et al. [81] analyzed the mRNA expression data in cancers from databases and found that MTF1 expression was significantly higher in CHOL and LIHC than in paired normal tissues, whereas its expression was lower in BRCA, COAD, KICH, KIRC, KIRP, LUAD, and THCA. MTF1 as a metalloregulator whose expression may guide precision metal-targeting therapies. Patients with breast cancer with lower MTF1 levels had worse overall survival and RFS rates [82]. This reveals that MTF1 can serve as a prognostic biomarker. MTF1 was lowly expressed in gastric cancer, and survival analyses showed that gastric cancer patients with low expression of MTF1 had shorter overall survival [83]. MTF1 expression emerged as a significant determinant of clinical outcomes in gastric cancer patients. Studies have shown that there is an inverse relationship between MTF1 transcript abundance and survival outcomes, with lower levels predicting improved overall survival and DFS in HCC patients [84]. Ji et al. [85] showed that MTF1 was upregulated in ovarian cancer and that ovarian cancer patients with high MTF1 expression have a low survival rate and are prone to disease recurrence. MTF1 drives ovarian cancer progression by enabling EMT-mediated metastasis; its expression pattern positions it as both a stratification biomarker for early detection and an actionable therapeutic target. Therefore, MTF1 has great potential for early diagnosis and clinical treatment. A thorough investigation of MTF1 could be of significant value in cancer prognosis assessment.
GLS
GLS primarily catalyzes the catabolism of glutamine, converting it into glutamate. It is involved in maintaining glutamate homeostasis. GLS and MTF1 may influence the cell’s sensitivity to copper ion deposition by affecting the intracellular balance of copper-binding substances such as glutathione and MT [86].
GLS catalyzes the deamidation of glutamine to glutamate, a metabolic precursor indispensable for sustaining neoplastic proliferation and biomass accrual in malignant cells [87]. GLS promotes tumor mutations in glioma cells, leading to poor patient prognosis and survival [88]. Moreover, GLS expression aligns with heightened immune infiltration and elevated specific immune signatures. These discoveries forge mechanistic foundations for molecularly tailored glioma immunotherapy advancement. GLS expression was significantly elevated in both cellular and clinical specimens of ESCC. Targeting GLS with the selective inhibitor CB-839 can effectively suppress the malignant phenotype and significantly inhibit the progression of ESCC. The interaction between GLS and PDK1 can inactivate PDH and accelerate glycolysis in ESCC cells [89]. Therefore, targeted inhibition of GLS thus emerges as a potential precision oncology strategy for ESCC patients. Research indicates that GLS was highly expressed in STAD, and patients with low GLS expression had better overall survival and PPS [49]. Yu et al. [90] found high expression of GLS1 in HCC. Furthermore, Li et al. [91] experimentally showed that GLS1 maintains the stemness of HCC cells through the ROS/Wnt/β-catenin signaling pathway. Inhibition of GLS1 significantly attenuated the stemness properties of HCC in both cellular and animal models, indicating its potential as a therapeutic target for disrupting cancer stem cell (CSC) populations. These insights crystallize GLS as a metabolic regulator, delineating actionable vulnerabilities and providing a therapeutic atlas.
CDKN2A
CDKN2A encodes two tumor suppressor proteins: p16 and p14ARF, which are located on chromosome 9. p16 typically inhibits CDK4 and CDK6 and activates Rb, thereby preventing the cell cycle transition from G1 to S phase. p14ARF activates the tumor suppressor gene p53 [92].
CDKN2A encodes P16, which is known to participate in a number of cellular processes, ranging from promoting tumorigenic expansion, blocking apoptosis induction, and generating chemotherapy insensitivity [93]. Researchers have found that CDKN2A promotes the angiogenesis phenotype in ESCC and forecasts unfavorable disease progression [94]. These results reveal CDKN2A as a potential prognostic biomarker for ESCC patients. The expression of CDKN2A was lower in normal tissues than in UCEC. Further prognostic analysis showed that UCEC patients with lower CDKN2A levels had better overall survival [95]. It performs well in predicting the prognosis of UCEC patients. Research shows that CDKN2A somatic copy number deletion (SCND) occurs frequently in the gastric cancer genome and may be a useful predictor of hematogenous metastasis in gastric cancer. CDKN2A SCND also reduces apoptosis and P53 expression while upregulating RB1 phosphorylation, making it a pathogenic factor in distant cancer metastasis [96]. Elevated CDKN2A expression was linked to poor survival outcomes in HCC. Notably, this gene may influence tumor progression by regulating immune infiltrating cells [93]. This study reveals the molecular mechanisms underlying the pathogenesis of HCC while launching a therapeutic discovery pipeline. The expression level of CDKN2A in normal intestinal epithelial cells was lower than that in tumor epithelial cells, and high expression of CDKN2A may indicate increased sensitivity to chemotherapy and combined radiotherapy and chemotherapy [97]. In summary, CDKN2A is effective in evaluating the prognosis of tumors.
The roles of ncRNAs and cuproptosis-related genes in cancer
In 2011, the competitive endogenous RNA (ceRNA) hypothesis was proposed [98], suggesting that circRNAs and lncRNAs can act as efficient miRNA sponges to sequester specific miRNAs. This competition effectively relieves the post-transcriptional repression of the miRNA’s target mRNAs, leading to their stabilization and increased expression [99]. Functioning as pivotal post-transcriptional regulators, ceRNA networks impact critical disease mechanisms, including cancer progression, metastasis, and therapy resistance [100], 101].
The regulatory mechanisms of ceRNA are shown in Figure 3.
The function of the ceRNA network.
The roles of ncRNAs and cuproptosis-related genes in esophageal cancer
Researchers have discovered that circ_0001093 expression was upregulated in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. Its high expression was connected with poor prognosis, lymph node metastasis in ESCC tissues. Downregulation of circ_0001093 inhibited glutamine metabolism in ESCC cells. The molecular mechanism revealed that circ_0001093 functioned as a molecular sponge for miR-579-3p, leading to the subsequent elevation of GLS protein levels. Importantly, either miR-579-3p inhibition or GLS overexpression effectively rescued the impaired glutamine metabolism resulting from circ_0001093 silencing in ESCC cells [102]. Therefore, when miR-579-3p is expressed low and GLS is highly expressed in ESCC cells and tissues, it promotes cancer cell proliferation, invasion, migration, and glutamine metabolism. In conclusion, the circ_0001093/miR-579-3p/GLS regulatory network can affect glutamine metabolism and thus ESCC progression.
The roles of ncRNAs and cuproptosis-related genes in breast cancer
Jiang et al. [82] documented significant downregulation of MTF1 in breast carcinoma specimens relative to normal mammary tissue. Lower MTF1 expression levels were linked to poorer RFS in breast cancer patients. The authors predicted six miRNAs as potential miRNA targets for MTF1 based on the results of database analysis. However, only miR-92b-3p showed differential expression in breast cancer. They then assessed its potential lncRNA targets and found that elevated levels of XIST in breast cancer were correlated with higher survival rates. Furthermore, Li et al. [103] found that the lncRNA XIST promoted apoptosis in breast cancer cells. Therefore, lncRNA XIST most likely targets miR-92b-3p. The lncRNA XIST/miR-92b-3p/MTF1 regulatory axis may play an important role in the treatment of breast cancer.
Reportedly, researchers have studied endocrine therapy (ET) resistance in ER+ breast cancer. They first identified DLD as a core cuproptosis-related gene (CRG) linked to ET resistance in ER+ breast cancer [104]. They first identified DLD as a core cuproptosis-related gene (CRG) linked to ET resistance in ER+ breast cancer. High DLD expression levels were found to correlate with a poorer prognosis. After intersecting 33 database-predicted miRNAs with 23 differentially expressed miRNAs in breast cancer cells, three miRNAs were found to be common. Analysis showed that patients with lower expression levels of hsa-miR-370-3p and hsa-miR-432-5p had a poorer prognosis. Furthermore, the expression of these two miRNAs was negatively linked to the expression of DLD, which is in accordance with the ceRNA network mechanism. Intersection analysis identified C6orf99 as a shared lncRNA between survival-associated lncRNAs and differentially expressed lncRNAs in breast cancer cells. The expression level of C6orf99 was positively linked to the expression of DLD mRNA, and negatively linked to the expression of hsa-miR-370-3p and hsa-miR-432-5p. Additionally, survival analysis showed that elevated C6orf99 expression was a predictor of poor clinical outcome. In summary, the establishment of the C6orf99/hsa-miR-370-3p and hsa-miR-432-5p/DLD regulatory axes lays a mechanistic foundation for the development of novel breast cancer therapeutic interventions.
The roles of ncRNAs and cuproptosis-related genes in lung adenocarcinoma
A research team selected the most important gene DLD through systematic screening, for further investigation. Using the StarBase database, they predicted 10 potential miRNA targets for DLD, and determined that low expression of miR-1-3p in LUAD correlates with prognosis. Patients with lower miR-1-3p expression have less difficult survival. Therefore, miR-1-3p is relevant for the treatment of DLD. Furthermore, database prediction of miR-1-3p-associated lncRNA targets revealed that only lncRNA UCA1 showed significant prognostic relevance in LUAD patients. Patients demonstrating high UCA1 expression exhibit inferior survival outcomes relative to counterparts with low expression [105]. Previous findings confirm that UCA1 promotes LUAD progression, which makes UCA1 relevant for the diagnosis and treatment of LUAD patients [106]. These results strongly suggest that the lncRNA UCA1/miR-1-3p/DLD axis is essential for the treatment of LUAD.
The roles of ncRNAs and cuproptosis-related genes in gastric cancer
Researchers have demonstrated that MALAT1 acts as an lncRNA target of miR-328-3p, showing upregulated expression in gastric cancer. Notably, high MALAT1 levels were linked to better survival rates in gastric cancer patients. Therefore, MALAT1 exerts tumor-suppressive effects when highly expressed. miR-328-3p is lowly expressed in gastric cancer. Patients with high miR-328-3p expression are less likely to survive [49]. These findings suggest that down-regulation of miR-328-3p inhibits cancer progression. Further investigations revealed that miR-328-3p acts as an upstream regulator targeting FDX1. Elevated FDX1 expression observed in gastric carcinoma specimens correlated with improved overall survival, implying a potential tumor-suppressive function of this gene in gastric oncogenesis. Therefore, the lncRNA MALAT1/miR-328-3p/FDX1 regulatory axis may play a critical role in gastric cancer progression.
Liu et al. [107] discovered that the low expression of PDHA1 in gastric cancer was linked to poor prognosis. The downregulation of PDHA1 promoted glycolysis and tumor progression in gastric cancer. By comparing common miRNAs, they identified 29 miRNAs that could potentially target PDHA1. Further analysis of their expression in clinical gastric cancer samples revealed that miR-21-5p was highly expressed in gastric cancer. Therefore, miR-21-5p may target PDHA1 in this context. Ectopic expression of miR-21-5p mimics in gastric cancer cells markedly suppressed PDHA1 expression at both transcriptional and translational levels. Concordantly, elevated miR-21-5p abundance observed in clinical specimens is inversely linked to PDHA1 downregulation. These data suggest that miR-21-5p directly targets PDHA1 mRNA and can promote glycolysis and gastric cancer cell proliferation.
The roles of ncRNAs and cuproptosis-related genes in hepatocellular carcinoma
Elevated PDHA1 expression was linked to adverse clinical outcomes in HCC patients. Through reverse prediction, a PDHA1-targeting miRNA (miR-1306-5p) was screened, showing negative correlation with overall survival in HCC patients. Additionally, the team identified SNHG3 as the upstream lncRNA targeting miR-1306-5p. qRT-PCR confirmed the upregulation of SNHG3 expression in HCC cell lines. In vitro experiments showed that SNHG3 significantly promoted the progression of HCC cells. Therefore, the researchers concluded that SNHG3 is a sponge for miR-1306-5p, which induces PDHA1 upregulation and ultimately leads to HCC progression. Based on PDHA1’s critical involvement in mitochondrial acetyl-CoA production via the pyruvate dehydrogenase complex, the authors proposed that SNHG3 acts as a sponge for miR-1306-5p, liberating PDHA1 mRNA from its inhibitory control [75]. Thus, upregulation of PDHA1 expression promotes the progression of the TCA cycle, generating more energy to support HCC progression. These findings pave the way for further mechanistic investigations.
Researchers observed that FDX1 expression was downregulated in HCC tissues. Critically, FDX1 abundance served as a positive prognostic determinant, with high-expression cohorts exhibiting superior survival. To identify potential lncRNAs that might regulate FDX1 expression, they intersected differentially expressed lncRNAs, FDX1-associated lncRNAs, and prognosis-related lncRNAs in HCC samples, yielding candidate genes. After using Starbase to identify potential miRNAs that might bind FDX1, hsa-miR-18a-5p was identified as being upregulated in tumor tissues and significantly associated with HCC prognosis [108]. Chen et al. [109] found that lncRNA RP5-833A20.1 could target miR-18a-5p to inhibit liver cancer progression via the AKT/ERK pathway. While, Li et al. [110] discovered that LINC02362 could mitigate the progression of HCC through the miR-516b-5p/SOSC2 axis. In addition, studies have shown that lncRNA linc00467 could regulate the miR-18a-5p/NEDD9 axis and thus play an oncogenic role in HCC. These findings highlight the role of LINC02362 and hsa-miR-18a-5p in HCC progression. Based on the ceRNA mechanism, the LINC02362/hsa-miR-18a-5p/FDX1 axis is crucial in HCC outcomes. hsa-miR-18a-5p expression was negatively linked to LINC02362 expression, whereas LINC02362 expression was positively linked to FDX1 expression [111]. These findings suggest that high expression of LINC02362 is linked to improved HCC prognosis, while hsa-miR-18a-5p overexpression portends diminished survival. These data implicate modulation of the LINC02362/hsa-miR-18a-5p/FDX1 regulatory axis as a promising strategy for HCC suppression.
The roles of ncRNAs and cuproptosis-related genes in clear cell renal cell carcinoma
Experiments have identified that FDX1 inhibited ccRCC cells growth. A marked downregulation of FDX1 was observed in ccRCC cellular compartments vs. paired paracancerous controls. The analysis shows that FDX1 downregulation may be caused by miRNA-mediated post-transcriptional regulation, which could lead to mRNA degradation. Initially, the authors selected 14 candidate miRNAs with differential expression in normal tissues and ccRCC tissues. Then, based on the miRDB prediction tool, miR-21-5p was identified as a hopeful candidate that targets FDX1 mRNA, and elevated miR-21-5p abundance constituted an independent prognostic determinant inversely correlated with overall survival duration in ccRCC patients [112]. Experimental validation confirmed that miR-21-5p could target FDX1 and thus effectively affect the microenvironment of ccRCC. In conclusion, the establishment of miR-21-5p/FDX1 axis in ccRCC offers the possibility of treating ccRCC.
The roles of ncRNAs and cuproptosis-related genes in colorectal carcinoma
MEG3 has been identified as a prognostic biomarker in colorectal carcinoma [113]. Zhang et al. [114] found that miR-103a-3p was significant for colorectal carcinoma diagnosis. In addition, Wang et al. [115] found that MEG3 was lowly expressed in colorectal carcinoma tumor tissues and cells. Meanwhile, miR-103a-3p was highly expressed, while PDHB was lowly expressed. In SW620 and HCT116 cells, the restoration of MEG3 expression inhibited cell viability, colony formation, and invasion, and upregulated the expression of ER stress-related proteins. Furthermore, high levels of MEG3 expression impede tumour growth and promote ER stress in vivo. At the molecular level, miR-103a-3p targets MEG3 and further targets PDHB. Functionally, miR-103a-3p blockade inhibited colorectal carcinoma in vitro by impacting cell proliferation. Additionally, the restoration of miR-103a-3p expression partly offset the inhibitory effect of MEG3 in CC cells. MEG3 acts as a sponge for miR-103a-3p, inhibiting colorectal carcinoma malignancy by inducing ER stress and upregulating PDHB, which suppresses cell proliferation and invasion.
The roles of ncRNAs and cuproptosis-related genes in pancreatic adenocarcinoma
It has been reported that DLAT acts as a negative survival regulator in PAAD pathogenesis. Strikingly, systematic miRNA screening designated hsa-miR-1179 as the unique transcript positively associated with patient survival. By analysing the database for lncRNAs related to hsa-miR-1179, the authors found that LINC00857 and NEAT1 were associated with hsa-miR-1179. Extended analytics established LINC00857 upregulation as an indicator of adverse clinical trajectories in pancreatic adenocarcinoma. Its expression magnitude exhibited significant concordance with DLAT transcript abundance, suggesting functional convergence [116]. Additionally, the results of in vitro experiments also verified that DLAT had a cancer-promoting effect on PAAD. Overall, the LINC00857/hsa-miR-1179/DLAT axis provides a basis for understanding the molecular mechanism of PAAD.
Figure 4 summarizes the mechanism by which ncRNAs regulate the expression of cuproptosis-related genes in tumors.
Flow chart depicting the mechanism underlying ncRNA involvement in the regulation of cuproptosis-related genes in tumors.
Future perspectives
The pervasive challenge of therapeutic resistance in oncology persistently undermines the clinical efficacy of both conventional and precision-directed cancer interventions. In recent years, research into GLP-1 agonists has also been gaining momentum for new therapeutic areas such as oncology [117], 118]. Meanwhile, as a natural compound, Prodigiosin fights cancer by modulating T cells and NK cells to counteract tumor immune escape [119]. Hinokitiol blocks cancer progression by targeting multiple molecular routes [120], 121]. Therefore, repurposing drugs as GLP-1-based therapy and giving various natural compounds as prodigiosin or hinokitiol, as prophylactic with immuno-modulatory effects, with a positive impact on cancer. In addition, emerging metallo-directed strategies offer novel solutions to chemotherapy resistance. such as the use of ion carriers and transition metal chelators [122]. Increasingly, copper complex-based drugs can specifically target drug-resistant cancer cells, thereby showing cytotoxicity. Building on this cuproptosis-inducing paradigm, we propose a bioinspired nanoplatform engineered to deliver cuproptosis-associated ncRNAs into tumor microenvironments. These synthetic biohybrid vectors concurrently modulate cuproptotic gene networks and spatiotemporally accelerate copper accumulation, thereby triggering tumor-selective copper-dependent death – a transformative approach for precision oncotherapy. However, the exact molecular mechanisms by which cuproptosis causes tumor cell death are still obscure. We need to continue research to explore the potential targets of cuproptosis in tumors, as this could increase the possibilities for cancer diagnosis, treatment, and prognostic monitoring.
Conclusions
This review initially addresses the mechanisms of cuproptosis, followed by a discussion of the regulatory role of ncRNAs in tumorigenesis. ncRNAs play crucial roles in human malignancies, acting as oncogenes or tumor suppressors to modulate cancer progression. We reviewed the expression patterns of CRGs in different tumors and their implications for the survival of cancer patients. Finally, we summarized recent findings on the molecular mechanisms by which ncRNAs influence tumor development through the regulation of cuproptosis-related genes in tumor cells (Table 1).
ncRNAs influence the molecular mechanism and clinical prospects of tumorigenesis and tumor development by regulating cuproptosis-related genes in tumor cells.
| Cancer type | ncRNA regulatory axis | Mechanism | ncRNA function | Experimental validation | Therapeutic potential | References |
|---|---|---|---|---|---|---|
| Esophageal squamous cell carcinoma | circ_0001093/miR-579-3p/GLS | Downregulation of circ_0001093 leads to the upregulation of miR-579-3p, which further downregulates GLS. | Inhibits proliferation, invasion, migration, and glutamine metabolism in esophageal squamous cell carcinoma. | in vitro evidence | Design a nanocarrier capable of efficiently delivering circ_0001093 inhibitors for diagnostic and therapeutic applications in esophageal squamous cell carcinoma. | [102] |
| Breast cancer | lncRNA XIST/miR-92b-3p/MTF1 | Upregulation of lncRNA XIST leads to the downregulation of miR-92b-3p, which further upregulates MTF1. | Suppresses breast cancer progression. | Not verified by experiment, based solely on bioinformatics analysis. | Design a nanocarrier capable of efficiently delivering lncRNA XIST agonists to inhibit breast cancer progression. | [82] |
| C6orf99/hsa-miR-370-3p and hsa-miR-432-5p/DLD | Downregulation of C6orf99 leads to the upregulation of hsa-miR-370-3p and hsa-miR-432-5p, which further downregulates DLD, | Reverses adjuvant endocrine therapy resistance in patients with estrogen receptor-positive breast cancer. | Not verified by experiment, based solely on bioinformatics analysis. | Design a nanocarrier capable of efficiently delivering C6orf99 inhibitors to reverse endocrine therapy resistance in breast cancer. | [104] | |
| Lung adenocarcinoma | lncRNA UCA1/miR-1-3p/DLD | Downregulation of lncRNA UCA1 leads to the upregulation of miR-1-3p, which further downregulates DLD. | Closely related to prognosis, clinical features, and immune infiltration in lung adenocarcinoma. | in vitro evidence | Design a nanocarrier capable of efficiently delivering lncRNA UCA1 inhibitors for the treatment of lung adenocarcinoma. | [105] |
| Gastric cancer | lncRNA MALAT1/miR-328-3p/FDX1 | Upregulation of the lncRNA MALAT1 leads to the downregulation of miR-328-3p, which further upregulates FDX1. | Suppresses gastric cancer development. | Not verified by experiment, based solely on bioinformatics analysis. | The combined application of lncRNA MALAT1 agonists and elesclomol can be used to inhibit the progression of gastric cancer. | [49] |
| miR-21-5p/PDHA1 | Downregulation of miR-21-5p leads to the upregulation of PDHA1. | Inhibits glycolysis and cell proliferation in gastric cancer. | in vitro evidence | Design a nanocarrier capable of efficiently delivering miR-21-5p inhibitors to suppress the proliferation of gastric cancer cells. | [107] | |
| Hepatocellular carcinoma | snhg3/miR-1306-5p/PDHA1 | Downregulation of snhg3 leads to the upregulation of miR-1306-5p, which further downregulates PDHA1. | Suppresses the proliferation, migration, and invasion of hepatocellular carcinoma cells. | in vitro evidence | Design a nanocarrier capable of efficiently delivering SNHG3 inhibitors to suppress the proliferation, migration, and invasion of hepatocellular carcinoma cells. | [75] |
| LINC02362/hsa-miR-18a-5p/FDX1 | Upregulation of LINC02362 leads to the downregulation of hsa-miR-18a-5p, which further upregulates FDX1. | Inhibits hepatocellular carcinoma proliferation and drives cuproptosis and oxaliplatin sensitivity. | in vitro evidence | The combined application of LINC02362 agonists and elesclomol can be used to inhibit the proliferation of hepatocellular carcinoma. | [108] | |
| Clear cell renal cell carcinoma | miR-21-5p/FDX1 | Downregulation of miR-21-5p leads to the upregulation of FDX1. | Suppresses the occurrence and progression of clear cell renal cell carcinoma. | in vitro evidence | The combination of a miR-21-5p inhibitor and elesclomol can be used to treat clear cell renal cell carcinoma. | [112] |
| Colorectal carcinoma | MEG3/miR-103a-3p/PDHB | Upregulation of MEG3 leads to the downregulation of miR-103a-3p, which further upregulates PDHB. | Inhibits the proliferation and invasion of colorectal cancer cells. | in vitro and in vivo evidence | Design a nanocarrier capable of efficiently delivering MEG3 agonists for inhibiting colon cancer. | [115] |
| Pancreatic adenocarcinoma | LINC00857/has-miR-1179/DLAT | Downregulation of LINC00857 leads to the upregulation of has-miR-1179, which further downregulates DLAT. | Suppresses the growth and invasion of pancreatic cancer cells. | in vitro evidence | Design a nanocarrier capable of efficiently delivering LINC00857 inhibitors to suppress the progression of pancreatic cancer. | [116] |
Cuproptosis plays a pivotal role in tumorigenesis and progression. Prior work has revealed that cuproptosis-related genes can inhibit tumor development by regulating glucose metabolism, apoptosis, cell cycle, and cancer-related signaling pathways. With further research into the mechanisms by which ncRNAs regulate the expression of cuproptosis-related genes, we may understand how ncRNAs trigger cuproptosis by binding to chemotherapy drugs such as elesclomol for cancer treatment. However, its feasibility is hindered by various factors such as different tumors, target specificity, delivery methods, efficiency, patient tolerance, and side effects. Therefore, incorporating our understanding of cuproptosis into precision oncology frameworks through the integration of multidisciplinary technologies spanning molecular biology, immunology, pharmacology, chemistry, and nanomedicine will pioneer innovative approaches to identify context-specific vulnerabilities in tumors and design tailored therapeutic interventions.
Funding source: the National Natural Science Foundation of China
Award Identifier / Grant number: Grant No. 82460515
Funding source: the Natural Science Basic Research Plan of Shaanxi Province
Award Identifier / Grant number: Grant No. 2025JC-YBMS-1088
Funding source: the Central Guidance on Local Science and Technology Development Fund of Xizang Autonomous Region
Award Identifier / Grant number: Grant No. LSKJ202447
Funding source: the Key R&D Projects of Xianyang Municipal Science and Technology Programme
Award Identifier / Grant number: Grant No. L2024-ZDYF-SF-0025
Funding source: the Graduate research innovation and practice projects of Xizang Minzu University
Award Identifier / Grant number: Grant No. Y2025140
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Research ethics: Not applicable. This study is purely textual and does not include human/animal data.
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Informed consent: Not applicable.
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Author contributions: Yuxin Du: Conceptualization, Writing- Original draft preparation. Zhendong Zhang: Conceptualization, Writing- Original draft preparation. Xinrui Hou: Investigation, data curation. Mingyuan Cao: Investigation, data curation. Xiaoping Wang: Supervision, Reviewing and Editing. All authors have read and agreed to the published version of the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors declare that they have no conflicts of interest to report regarding the present study.
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Research funding: This work was supported by the National Natural Science Foundation of China (Grant No. 82460515), the Natural Science Basic Research Plan of Shaanxi Province (Grant No. 2025JC-YBMS-1088), the Central Guidance on Local Science and Technology Development Fund of Xizang Autonomous Region (Grant No. LSKJ202447), the Key R&D Projects of Xianyang Municipal Science and Technology Programme (Grant No. L2024-ZDYF-SF-0025) and the Graduate research innovation and practice projects of Xizang Minzu University (Grant No. Y2025140).
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Data availability: No datasets were generated or analysed during the current study.
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