Search Results (97)

The homeostasis balance of copper, as an essential trace element for life activities, is crucial for maintaining the normal function of cells. Cuproptosis, discovered in recent years, is a novel type of programmed cell death triggered by the accumulation of excessive copper ions in mitochondria. The core mechanism lies in that copper ions, after being reduced by ferridoxin (FDX1), directly target and induce the oligomerization of the acylated tricarboxylic acid (TCA) cycle enzyme, thereby triggering fatal protein toxic stress. This distinctive mechanism operates independently of other recognized pathways of cell death, offering a novel perspective for elucidating the pathological processes underlying various diseases. A review of pertinent research conducted over the past four years reveals that cuproptosis is not only significantly implicated in the onset, progression, and treatment resistance of tumors but is also intricately associated with diverse pathological processes, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, and immune abnormalities. This article conducts a multi-level summary from molecular mechanisms to physiological and pathological significance; deeply explores the interaction between cuproptosis and various subcellular structures, as well as their complex signal regulatory network; and systematically expounds the cutting-edge strategies for treating cuproptosis, including traditional copper chelating agents, ion carriers, and copper-based nanomedicines, with a particular focus on the latest progress in the field of natural product research. This review has systematically summarized the therapeutic potential demonstrated by numerous natural active ingredients when precisely regulating the cuproptosis pathway to provide a theoretical reference for future research in this field. Full article

Immunogenic cell death (ICD) is a programmed pathway leading to cell death and promotion of immunological responses. Melanoma is resistant to chemotherapy and radiotherapy (RT). Disulfiram (DSF), which forms complexes with copper (Cu), has been shown to induce ICD of many tumor types. Here, we aim to investigate whether DSF/Cu combined with irradiation (IR) can induce ICD and exert anti-cancer effects in melanoma. In vitro experiments, treatment of MV3 and B16F10 melanoma cells with DSF/Cu + IR significantly increased the cellular apoptosis and increased ICD markers: damage-associated molecular pattern molecule (DAMP) exposure and release, including calreticulin cell surface expression, high-mobility group box 1 (HMGB1) release, and decreased intracellular ATP levels. In addition, DSF/Cu combined with IR treatment inhibited tumor growth and enhanced tumor-infiltrating immune cells in the B16F10-bearing C57BL/6 model. Our findings reveal that combining IR with DSF/Cu induces ICD and inhibits tumor growth in melanoma, providing a promising strategy to overcome the inherent resistance of RT in melanoma. Full article

Background: Triple-negative breast cancer (TNBC) remains primarily treated with chemotherapy due to the lack of effective therapeutic targets, but this approach carries significant systemic toxicity and a high risk of drug resistance. Curcumin (Cur), despite its multifaceted antitumor activity, faces limitations in clinical application due to poor water solubility and weak targeting properties. This study aims to develop a folate/mitochondria dual-targeted curcumin–copper chelate liposome (Cu-Cur DTLPs) formulation that enables copper accumulation within tumor cells and induces copper-mediated cell death, thereby providing an effective and relatively low-toxicity therapeutic strategy for triple-negative breast cancer. Methods: Curcumin–copper chelates (Cu-Cur) were first synthesized and characterized using mass spectrometry, NMR, and infrared spectroscopy. Subsequently, dual-targeted liposomes (Cu-Cur DTLPs) were prepared via the thin-film dispersion method, with systematic evaluation of particle size, zeta potential, encapsulation efficiency, and in vitro release profiles. In vitro cytotoxicity was assessed against 4T-1 and MDA-MB-231 cells using the MTT assay. In a 4T-1 tumor-bearing BALB/c mouse model, comprehensive evaluation of targeting efficiency, antitumor efficacy, and mechanisms of action was conducted via in vivo imaging, tumor volume monitoring, immunohistochemistry (detecting FDX1 and DLAT proteins), and TUNEL staining. Results: Cu-Cur DTLPs with a uniform particle size of approximately 104.4 nm were successfully synthesized. In vitro and in vivo studies demonstrated that compared to free curcumin and conventional liposomes, Cu-Cur DTLPs significantly enhanced drug accumulation in tumor tissues and exhibited effective tumor growth inhibition. Mechanistic studies confirmed that this formulation specifically accumulates copper ions within tumor cells, upregulates FDX1, promotes DLAT oligomerization, and induces mitochondrial dysfunction, thereby driving copper death. TUNEL staining ruled out apoptosis as the primary mechanism. Safety evaluation revealed no significant toxicity in major organs. Conclusions: The Cu-Cur DTLPs developed in this study effectively induce copper-mediated death in TNBC through a dual-targeted delivery system, significantly enhancing antitumor activity with favorable safety profiles. This establishes a highly promising novel nanotherapeutic strategy for TNBC treatment. Full article

Copper (Cu) is an essential element required by all living cells, where it supports critical enzymatic and signaling functions. In cancer, this balance is often disrupted, creating vulnerabilities that can be therapeutically exploited. Changes in Cu availability have been shown to influence key immunoregulatory pathways, including those involved in inflammation, cell death, and immune evasion. Notably, Cu can drive expression of programmed death ligand 1 (PD-L1), contributing to immunosuppression, while also promoting immunogenic cell death, which stimulates adaptive immune responses. These dual effects highlight the complexity and therapeutic potential of Cu-based interventions, particularly in the context of immune modulation and toxicity. This review argues that Cu-based nanomedicines can selectively deliver high concentrations of bioactive Cu to tumor cells, inducing cell death and triggering adaptive immune responses. We summarize current knowledge on Cu’s roles in cancer and immunity, emphasizing recent insights into how these intersect through Cu-mediated modulation of anticancer immune pathways. Finally, we explore the clinical potential of Cu-based nanomedicines to convert immunologically “cold” tumors into “hot” ones, thereby improving responses to immunotherapy. Realizing this potential will depend on the thoughtful integration of Cu delivery approaches with existing immunotherapeutic strategies. Full article

Mitochondrial oxidative phosphorylation serves as a critical driving force in the progression of ovarian cancer. Recent studies have demonstrated that copper induces mitochondrial-dependent programmed cell death by directly binding to the thioacylated components of the tricarboxylic acid (TCA) cycle. The involvement of copper in OXPHOS complex IV, a rate-limiting step in the mitochondrial respiratory chain, suggests that the role of mitochondria in mediating copper-induced cell death can be further elucidated through the study of OXPHOS complex IV. The findings of this study indicate that the cuproptosis process in ovarian cancer, induced by Elesclomol, is associated with mitochondrial complex IV, with LRPPRC identified as a crucial factor. Following Elesclomol treatment of ovarian cancer cells, there was a notable increase in mitochondrial reactive oxygen species (ROS), a significant accumulation of the copper death marker protein DLAT, and a marked decrease in the lipoic acid synthesis-related protein FDX1. Furthermore, the expression levels of copper ion transporters ATP7B and CTR1, which are involved in the assembly and translation of complex IV, as well as the core subunit MTCO1 of complex IV, the copper chaperone protein SCO1, and the interacting protein LRPPRC, were significantly diminished. Inhibition of the IV-stabilizing protein LRPPRC in the ovarian cancer cell lines A2780 and SKOV3 through RNA interference resulted in increased sensitivity to Elesclomol. Concurrently, the expression levels of FDX1, LIAS, LIPT1, SCO1, and MTCO1 decreased significantly. These findings suggest that LRPPRC plays a role in inhibiting the expression of lipoic acid and copper chaperone proteins during Elesclomol-induced copper death in ovarian cancer. This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer. Full article

Oxidative stress (OS) is increasingly recognized as a dynamic disturbance of cellular redox networks rather than a simple imbalance between oxidants and antioxidants. In this context, ferroptosis and cuproptosis—two regulated and metal-dependent forms of cell death—emerge as key mechanisms linking OS to metabolic dysfunction, inflammation, and tissue injury. This review integrates findings from biochemical, lipidomic and metallomic studies to describe how lipid peroxidation (LPO), glutathione (GSH)–Glutathione Peroxidase 4 (GPX4) activity, ferritinophagy, copper-induced mitochondrial protein lipoylation, and altered communication between organelles generate distinct redox signatures across diseases. By examining cutaneous, metabolic, cardiovascular, infectious, neurodegenerative, and oncologic conditions, we outline the shared redox pathways that connect iron- and copper-dependent cell death to systemic inflammation, immune dysregulation, and chronic tissue damage. Common oxidative markers—such as oxidized phospholipids, lipid aldehydes including 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA), and systemic metal imbalance—are highlighted as potential indicators of disease severity and as emerging therapeutic targets. We also discuss innovative analytical tools, including redox lipidomics, metallomic profiling and artificial-intelligence (AI)-based classification approaches, which improve the characterization of redox vulnerability and may guide the development of precision redox therapies. Overall, ferroptosis and cuproptosis represent unifying mechanisms that connect OS to multisystem disease and provide new opportunities for diagnostic refinement and targeted antioxidant-based interventions. Full article

Granular copper oxide nanoparticles (CopOx NPs), synthesized via laser ablation (100 nm, ζ-potential +30 mV), were introduced into photolithographic polymethyl methacrylate (PMMA) resin at concentrations of 0.001–0.1%. The resulting composite material enables the fabrication of high-resolution (up to 50 μm) parts with a high degree of surface quality after polishing using the MSLA method. CopOx NPs increased the degree of resin polymerization (decrease by almost 4× in unpolymerized components at 0.1% CopOx NPs) and induced the in situ formation of self-organized periodic structures visible under a modulation interference microscope. The composite samples exhibit pronounced oxidative activity: they intensify the generation of hydrogen peroxide and hydroxyl radicals and cause the oxidative modification of biomolecules (formation of 8-oxoguanine in DNA and long-lived reactive forms of proteins). A key property of the materials is their selective biological activity. While lacking cytotoxicity for human fibroblasts, they exhibit a strong antibacterial effect against E. coli, leading to cell death within 24 h. Thus, the developed composite photolithographic resin combines improved technological characteristics (high printing resolution, degree of polymerization) with functional properties (selective antibacterial activity) and holds promise for application in biomedicine, as well as in the food and agricultural industries. Full article

Background: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by limited therapeutic options and poor prognosis. Temozolomide (TMZ) remains the standard chemotherapy; however, its effectiveness is often hindered by the development of acquired resistance. Cuproptosis, a recently identified copper-dependent form of regulated cell death, has emerged as a potential therapeutic target. The synergistic effects of TMZ and copper, as well as the molecular mechanisms underlying their combined action, remain unclear. This study aimed to investigate the role of tripartite motif-containing protein 14 (TRIM14) and its downstream effector ATP7A in mediating TMZ- and copper-induced cuproptosis in glioma. Methods: We employed in vitro cellular assays, in vivo xenograft models, bioinformatic analysis, immunofluorescence staining, Western blotting, and co-immunoprecipitation experiments to examine the functional involvement of TRIM14 and ATP7A during combined TMZ and copper chloride (CuCl₂) treatment. Intracellular copper levels and cuproptosis markers, including Dihydrolipoamide S-acetyltransferase (DLAT), were assessed to evaluate copper-dependent cytotoxicity. Results: TMZ combined with CuCl₂ markedly enhanced cuproptosis in glioma cells, as evidenced by increased DLAT expression and elevated intracellular copper accumulation. This combination treatment significantly suppressed TRIM14 expression, downregulated the TRIM14–ATP7A axis, and inhibited non-canonical NF-κB signaling. Co-immunoprecipitation assays further revealed a potential interaction between TRIM14 and ATP7A, suggesting that TRIM14 may modulate ATP7A stability or activity. Conclusions: Our findings indicate that TMZ and copper synergistically induce cuproptosis in GBM by disrupting the TRIM14–ATP7A regulatory axis and promoting intracellular copper accumulation. Targeting TRIM14 or ATP7A to enhance cuproptosis may represent a promising therapeutic strategy to overcome TMZ resistance and improve clinical outcomes in GBM patients. Full article

Background/Objectives: Cuproptosis, a newly discovered form of programmed cell death, is dependent on the regulation of copper ions. The roles and mechanisms of cuproptosis-related genes (CRGs) in the instability of atherosclerotic plaques are still unclear. Methods: GEO microarray datasets were downloaded to analyze stable and unstable human carotid artery plaques. Differential expression analysis was performed to screen for CRGs from the Molecular Signatures Database (MSigDB). Machine learning was applied to identify key genes and cluster unstable plaque genes. The identified genes were verified by immunohistochemistry (IHC) of human carotid plaque samples, and the effect of ATOX1 on cuproptosis was detected in human umbilical vein endothelial cells (HUVEC). Results: This study identified 27 CRGs differentially expressed between stable and unstable plaques. Five characteristic genes (LC3A, ATP7B, ATOX1, CTR1, and NLRP3) were selected by machine learning. A diagnostic model for unstable plaques was developed based on these genes. The expression of ATOX1 and NLRP3 was increased, while LC3A and ATP7B were decreased in unstable plaques. However, there was no significant change in CTR1. The Cell Counting Kit-8 (CCK-8) assay indicated that inhibiting ATOX1 reduced CuSO₄-induced HUVEC death. Conclusions: CRGs appear to influence atherosclerotic plaque formation. Five key genes (LC3A, ATP7B, ATOX1, CTR1, NLRP3) were identified as being differentially expressed in unstable plaques. Cluster analysis uncovered two subtypes (C1, C2) linked to cuproptosis and immune infiltration in unstable plaques. These genes likely affect atherosclerosis progression by influencing immune cell infiltration, thus impacting plaque stability. Furthermore, the cuproptosis-related gene ATOX1 can regulate CuSO₄-induced HUVEC death. This study contributes to predicting plaque instability and offers potential diagnostic and therapeutic targets. Full article

Sarcopenia is a common age-related skeletal muscle disorder that lacks diagnostic and therapeutic options. Emerging evidence suggests that cuproptosis, a copper-dependent form of regulated cell death, contributes to muscle atrophy, yet the underlying associations remain poorly understood. To address this gap, we integrated two GEO datasets (GSE1428 and GSE25941) for differential expression analysis and applied weighted gene co-expression network analysis (WGCNA) to identify disease-related modules. Cuproptosis-related genes (CRGs) from GeneCards database were intersected with DEGs and WGCNA gene modules to obtain sarcopenia-associated cuproptosis DEGs (SAR-CUP DEGs). Functional enrichment was performed using GO, KEGG, GSEA and GSVA. Hub genes were further identified through three machine learning algorithms (LASSO, RF, and SVM). Regulatory networks were constructed via NetworkAnalyst and GeneMANIA database. A diagnostic model was also developed and later validated in an independent dataset (GSE136344). Experimental validation was performed in a D-galactose-induced sarcopenia cell model. We identified 367 DEGs and 7 co-expression modules, among which 14 SAR-CUP DEGs were mainly enriched in mitochondrial energy metabolism pathways. Machine learning methods highlighted SLC25A12 and PABPC4 as hub genes. Regulatory network analysis revealed key modulators, such as FOXC1, miR-16-5p, GOT2, and GOT1. Diagnostic performance analysis demonstrated strong predictive value for SLC25A12 (AUC = 0.879) and PABPC4 (AUC = 0.858), and RT-qPCR confirmed their downregulation in the sarcopenia cell model (p < 0.01). In conclusion, SLC25A12 and PABPC4 are promising biomarkers linking copper metabolism dysregulation with sarcopenia, offering potential targets for diagnosis and therapy. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) is among the most aggressive subtypes, lacking estrogen, progesterone, and HER2 receptors, which limits the efficacy of targeted therapies. Standard treatments often fail due to rapid drug resistance and poor long-term outcomes. Repurposing approved drugs with anticancer potential offers a promising alternative. Disulfiram (DSF), an FDA-approved alcohol-aversion drug, forms a copper complex [Cu(DDC)₂] with potent anticancer activity, but its clinical translation is hindered by poor solubility, limited stability, and inefficient delivery. Methods: Here, we present an amphiphilic dendrimer-stabilized [Cu(DDC)₂] nanoparticle (NP) platform synthesized via the stabilized metal ion ligand complex (SMILE) method. Results: The optimized nanocarrier achieved high encapsulation efficiency, enhanced serum stability, and potent cytotoxicity against TNBC cells. It induced immunogenic cell death (ICD) characterized by calreticulin exposure and ATP release, while modulating the tumor microenvironment by downregulating MMP-3, MMP-9, VEGF, and vimentin, and restoring epithelial markers. In a 4T1 TNBC mouse model, systemic [Cu(DDC)₂] NP treatment significantly inhibited tumor growth without combinational chemo- or radiotherapy. Conclusions: This DSF-based metal–organic NP integrates drug repurposing, immune activation, and tumor microenvironment remodeling into a single platform, offering strong translational potential for treating aggressive breast cancers. Full article

Background: Cisplatin is a powerful treatment for cancer; however, its clinical application is compromised due to its potential for nephrotoxicity. The development of nephroprotective agents is hindered mainly due to the lack of understanding of the exact underlying mechanism. Additionally, the identification of safe nephroprotective agents that can be used as an adjunct to cisplatin is necessary. Methods: Rats were pretreated with thymol (60 mg/kg, orally) daily for two weeks and received a single cisplatin injection (8 mg/kg, i.p.) on the seventh day to induce nephrotoxicity. Results: Thymol prevented cisplatin-induced renal injury and restored serum creatinine and blood urea nitrogen. The renoprotective activity of thymol was further validated by histopathological studies, as demonstrated by the preserved architectures of the glomeruli, proximal, and distal convoluted tubules. Oxidative stress plays an important role in the pathophysiology of nephrotoxicity. Herein, cisplatin administration increased lipid peroxides and depleted the cellular antioxidant defense mechanisms (GSH, SOD, Nrf2, and HO-1). Interestingly, thymol remarkably ameliorated these alterations and restored oxidative status. We further examined the impact of cisplatin and/or thymol on cuproptosis, a distinct type of cell death associated with the excess intracellular accumulation of copper which is aggravated by oxidative stress. Pretreatment with thymol blunted the cisplatin-induced upregulation of genes associated with cuproptosis, including SLC31A1, DLAT, FDX1, LIAS, and ATP7A, as well as FDX1 protein expression. Furthermore, the molecular docking studies of thymol demonstrated favorable fitting and interactions with the conservative amino acids of FDX-1, DLAT, and ATP7A. This further supports the inhibitory effect of thymol on cuproptosis, which underlies its protective properties. Conclusions: This study illustrates that cuproptosis and oxidative stress play crucial roles in the development and progression of cisplatin-induced nephrotoxicity, and the protective activity of thymol is attributed, at least in part, to blunting these mechanisms. Full article

The use of copper nanoparticles (CuNPs) seems to be an alternative therapeutic strategy for cancer therapy due to low-cost synthesis and anticancer activity. In this work, CuNPs’ effects were tested in various concentrations on two types of cells: mesenchymal stem cells (MSCs) and a breast cancer cell line, SKBR3. The concentrations (0.25 mM, 0.5 mM, 1 mM and 2 mM) were first tested on an impedance-based cytotoxicity assay and then used in further cellular metabolic assays. Next, several techniques were applied to test the chosen concentrations: assessment of apoptosis, intracellular reactive oxygen species (ROS) levels, oxidative stress-related gene expression, assessment of mitochondrial respiration and fatty acid methyl ester (FAME) profile evaluation. The higher CuNP concentrations tested on the SKBR3 cell line showed a dose-dependent decrease in the cell index. SKBR3 cells displayed increased CAT and SOD expression, revealed by strong dose-dependent fluorescence. Annexin/PI staining confirmed increased SKBR3 cell death induced by the higher doses of CuNPs. SKBR3 revealed higher baseline respiratory capacity compared to MSCs. Fatty acid methyl esters (FAMEs) are in higher abundance in MSCs compared to the SKBR3 cell line. The different metabolic response in the tested cells to the CuNPs’ presence could help establish a future personalized treatment for breast cancer patients. Full article

Cuproptosis is a newly identified type of copper (Cu)-dependent programmed cell death (PCD), triggered when Cu directly interacts with the lipoylated components of the tricarboxylic acid (TCA) cycle, and it has shown significant antitumor potential. However, challenges such as insufficient Cu accumulation in tumor cells, systemic toxicity, and the lack of specific carriers for effectively inducing cuproptosis hinder its practical application. Inorganic nanoparticles (INPs) present a promising solution due to their unique ability to target specific areas, potential for multifunctional modification, and controlled release capabilities. Their distinctive physicochemical properties also enable the integration of synergistic multimodal cancer therapies. Therefore, utilizing INPs to induce cuproptosis represents a promising strategy for cancer treatment. This review systematically elucidates the regulatory mechanisms of Cu homeostasis and the molecular pathways underlying cuproptosis, thoroughly discusses current INP-based strategies designed to trigger cuproptosis, and comprehensively examines the multi-modal synergistic antitumor mechanisms based on cuproptosis. Finally, we also address the current challenges and future perspectives in developing clinically applicable nanoplatforms aimed at harnessing cuproptosis for effective cancer therapy. Full article

Steatotic liver disease (SLD) has become one of the most prevalent chronic liver diseases, representing a significant health burden worldwide. The complex pathogenesis of SLD results in a lack of specific therapeutic targets and effective drug treatment modalities. Copper (Cu) is a trace element that plays a critical role in various physiological processes, particularly hepatic metabolism. Meanwhile, Cu overload can induce cellular toxicity, which is generally explained by its capacity to induce oxidative damage. In 2022, a novel form of programmed cell death, designated as cuproptosis, was identified. In essence, excess Cu ions bind to the lipoylated components of the tricarboxylic acid cycle, resulting in proteotoxic stress and subsequent cell death. The role of cuproptosis in the pathologies of Cu overload-induced diseases has gained considerable attention. However, the association between SLD and Cu overload, particularly cuproptosis, remains to be elucidated. This review provides a concise overview of cuproptosis. The significance of Cu overload in SLD, as well as the potential association between cuproptosis and SLD, is explored. This review aims to offer insights into the potential of cuproptosis as a therapeutic target for SLD. Full article