Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Cuproptosis-a novel cell death mechanism-is an innovative strategy for tumor therapy. However, the insufficient efficacy of cuproptosis, primarily owing to the low sensitivity of tumor cells to Cu ions, remains a major challenge. In this study, we design TiCuMOF@PEG@l-Arg@TPP (TCPAT) nanoparticles to facilitate self-sensitized cuproptosis for anti-tumor therapy through the dual upregulation of p53. TiMOF serves as a microwave sensitizer by generating reactive oxygen species (ROS). Notably, the uniformly distributed Cu ions within the MOF serve as co-catalysts to provide reactive sites that enhance ROS generation. Additionally, the ROS generated are utilized to oxidize l-arginine, thus resulting in the release of nitric oxide (NO), which has a long half-life and diffusion distance, thereby enabling it to penetrate deep into the tumor regions that are typically inaccessible to ROS. Furthermore, TCPAT not only induces cuproptosis but also leverages the efficiently generated ROS and cascade-released NO for the dual upregulation of p53. This upregulation subsequently inhibits glycolysis, increases cellular sensitivity to Cu ions, and facilitates self-sensitized cuproptosis. Consequently, the self-sensitized cuproptosis strategy, dependent on the efficient generation of ROS, presents a promising avenue for tumor therapy based on cuproptosis mechanisms.

Cancer metastasis and recurrence remain a regular cause of postoperative death in patients, implying that extra consolidation treatment strategies are needed. Here, a cuproptosis nanoprodrug, termed as Lipo@CP@DQ NPs, is developed to initiate self-promoted cascade reactions to achieve the combinational effect of cuproptosis, in situ chemotherapy, and oxidative stress amplification for effectively suppressing tumor recurrence and metastasis after postoperative treatment. Lipo@CP@DQ NPs are fabricated by loading copper peroxides (Cu2O2, CP) and hydrogen peroxide (H2O2)-repsonsive prodrug DQ into liposomal nanoparticles. Lipo@CP@DQ NPs rapidly dissociate in the acidic tumor microenvironment to release copper ions, H2O2, and prodrug DQ. Subsequently, the excessive accumulation of Cu ions induces cuproptosis and produces highly cytotoxic hydroxyl radicals (•OH). Meanwhile, the self-supplied H2O2 catalyzes the decomposition of DQ to diethyldithiocarbamate (DTC), which is chelated with self-supplied Cu ions to form the anticancer compound, Cu(DTC)2. The another decomposition product, quinone methide (QM), acts as a glutathione (GSH) scavenger for oxidative stress amplification. The synergistic effect of Lipo@CP@DQ NPs-mediated cuproptosis, in situ chemotherapy, and oxidative stress amplification effectively inhibits the growth and postoperative recurrence of triple-negative breast cancer. This work furnishes a strategy for developing cuproptosis-based nanomedicines for effective antitumor treatment after surgery.

Triple-negative breast cancer (TNBC) presents therapeutic challenges due to its aggressive, drug-resistance, and low immunological reactivity. Cuproptosis, an emerging therapeutic modality, is a promising strategic intervention for treating TNBC. Nonetheless, the effectiveness of cuproptosis is compromised by tumor adaptations, including the Warburg effect, increased intracellular glutathione (GSH), and copper efflux, thus breaking the barrier of cuproptosis is the basis for developing cuproptosis-based clinical therapies. Herein, a self-accelerating strategy utilizing a pH-responsive copper framework encapsulating glucose oxidase (GOx), modified with polyethylene glycol (PEG) and tumor-penetrating peptide (tLyp1) has been developed. Upon reaching the acidic tumor microenvironment, the released GOx increases intracellular acidity and hydrogen peroxide (H2O2). The elevated intracellular GSH and H2O2 serve as "fuel" to amplify the copper-based catalytic within tumor cells. Concurrently, the reduction of copper efflux proteins (ATP7B) and the depletion of GSH lead to copper overload in tumor cells, leading to cuproptosis via copper overload, mitochondrial disruption, and Fe-S protein instability. This constellation of interrelated events constitutes a potent "Copper Bomb," which concurrently triggers the immune system and effectively kills the tumor. It robustly engages innate and adaptive immunity via the release of mitochondrial DNA, facilitating the cGAS-STING pathway and precipitating immunogenic cell death. This process reverses the immunosuppressive tumor microenvironment, eliminates tumor cells, and suppresses metastasis, thus offering a novel therapeutic modality for the comprehensive treatment of triple-negative breast cancer (TNBC).

The spatiotemporal sequential treatment strategy of promoting rapid separation of charge carriers, amplifying oxidative stress, increasing the low content of intracellular Cu, enhancing cuproptosis, and cascading activation of immunotherapy is considered one of the most effective techniques for improving the comprehensive therapy of tumors. Herein, copper tungstate (CuWO₄, CWO) nanoparticles with ultrasmall bandgap (1.71 eV) is developed as both piezoelectric-catalysis agents and copper nanocarriers for synergistic sono-enhanced cuproptosis. Owing to the unique bandgap microstructure, exposure to ultrasound (US) significantly increase the generation of reactive oxygen species (ROS) and the release of Cu2+ from CWO. Additionally, ≈60% of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) are consumed in situ, leading to oxidative stress, ferroptosis, and cuproptosis in cancer cells. This cascading approach induces substantial mitochondrial dysfunction and the release of damage-associated molecular patterns (DAMPs), which promotes immunogenic cell death (ICD) and augments antitumor immunity. Both in vitro and in vivo studies have shown that this sono-enhanced cuproptosis-based therapy could effectively suppress tumor growth. Overall, this study investigates a novel Structure-Function therapeutic approach that combines piezoelectric catalysis, ferroptosis, cuproptosis, and cascade activation of immune regulation, opening up new possibilities for addressing the challenges associated with conventional cuproptosis therapy.

Cuproptosis is a new mode of cell death that is closely related to mitochondrial stress. The purpose of this study is to investigate the amount of copper, copper-associated genes DLAT and FDX1 oxidative stress (OS) status in obesity. Since there is a close relationship between OS and cuproptosis, evaluating the effect of various strategies to reduce OS, including quercetin (QUER) and caloric restriction (CR), is another goal of this study. In this study, 30 male BALB-C mice aged 8 weeks and weighing 25 g, including the groups receiving normal diet (ND), ND with QUER (15 mg/kg, IP) and CR, a high-fat diet (HFD) with the QUER, CR or a combination of both were used. The activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione reductase (GR), amount of copper in the liver and kidney tissues, and expression of DLAT and FDX1 genes were measured in all studied groups. The amount of copper in the liver and kidney tissue as well as the expression of FDX1 and DLAT in the HFD group increased significantly compared with the ND group. QUER, CR or their combination could significantly reduce the amount of copper as well as the expression of FDX1 and DLAT in liver and kidney tissues. QUER and CR, also significantly increased the activity of GR, SOD and GPX in serum, liver, and kidney tissues. Based on the results, QUER, CR and especially the simultaneous use of both, was able to reduce the amount of copper and its related cuproptosis. These effects may reduce cuproptosis-associated cell death. Therefore, the use of antioxidants and CR may be a promising solution to protect the human body against the effects of cuproptosis in conditions like obesity.

A significant role in many cancers is played by cuproptosis, a new term for the copper-dependent regulatory cell death pattern. However, as a new research hotspot, the cuproptosis-related lncRNAs (CRLs) associated with regulation in oral squamous cell carcinoma (OSCC) patients are currently not well understood.

Long noncoding RNA (lncRNA) data were downloaded from the Cancer Genome Atlas database (TCGA). The 'LIMMA' package in R software was used to screen for differential expression of CRLs. LASSO regression and COX regression models were used to construct prognostic signature based on 4 prognostic CRLs. Finally, the relationship of risk characteristics with immune correlation analysis, somatic mutations, PCA, biological molecular pathways and drug sensitivity was investigated.

A cuproptosis-related lncRNAs prognostic signature was developed by us. Based on the risk scores, the OSCC samples were split into high- and low-risk groups using this signature. The two risk groups differed significantly in immune functions, drug sensitivity, and overall survival. The risk model showed better prognostic predictive power compared to the traditional clinicopathological signature. By qPCR trial, we also verified the expression of STARD4-AS1 in OSCC cell lines and tissues was in line with our results from this experimental screen. Through cell experiments, we have confirmed that knocking down STARD4-AS1 promotes the proliferation and migration ability of OSCC cells.

The CRLs signature contributes to new understandings of the treatment of OSCC and is a rubost biomarker for predicting the prognosis of patients with OSCC.

Multiple machine learning techniques were employed to identify key long non-coding RNA (lncRNA) biomarkers associated with cuproptosis in Diffuse Large B-Cell Lymphoma (DLBCL). Data from the TCGA and GEO databases facilitated the identification of 126 significant cuproptosis-related lncRNAs. Various feature selection methods, such as Univariate Filtering, Lasso, Boruta, and Random Forest, were integrated with a Transformer-based model to develop a robust prognostic tool. This model, validated through fivefold cross-validation, demonstrated high accuracy and robustness in predicting risk scores. MALAT1 was pinpointed using permutation feature importance from machine learning methods and was further validated in DLBCL cell lines, confirming its substantial role in cell proliferation. Knockdown experiments on MALAT1 led to reduced cell proliferation, underscoring its potential as a therapeutic target. This integrated approach not only enhances the precision of biomarker identification but also provides a robust prognostic model for DLBCL, demonstrating the utility of these lncRNAs in personalized treatment strategies. This study highlights the critical role of combining diverse machine learning methods to advance DLBCL research and develop targeted cancer therapies.

Intracellular copper levels should be maintained within a controlled range to obtain copper homeostasis. Cuproptosis, a newly discovered form of cell death, occurs when excessive copper ions bind to the lipoylated enzymes in the tricarboxylic acid cycle, which leads to lipoylated protein aggregation, proteotoxic stress, and ultimately cell death. Herein, we summarize the current knowledge regarding copper metabolism, the discovery and molecular mechanism of cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various liver diseases, including hepatocellular carcinoma (HCC), Wilson disease (WD), metabolic-associated fatty liver disease (MAFLD), liver fibrosis, hepatic ischemia-reperfusion injury (HIRI) and drug-induced liver injury (DILI). Understanding the mechanism of cuproptosis can not only provide deeper insights into the pathogenesis of liver diseases but also open up new avenues for the development of targeted therapies.

Hepatocellular carcinoma (HCC) is the main phenotype of liver cancer with a poor prognosis. Copper is vital in liver function, and HCC cells rely on it for growth and metastasis, leading to cuproplasia. Excessive copper can induce cell death, termed cuproptosis. Tumor microenvironment (TME) is pivotal in HCC, especially in immunotherapy, and copper is closely related to the TME pathogenesis. However, how these two mechanisms contribute to the TME is intriguing.

We conducted the latest progress literature on cuproplasia and cuproptosis in HCC, and summarized their specific roles in TME and treatment strategies. The mechanisms of cuproplasia and cuproptosis and their relationship and role in TME have been deeply summarized. Cuproplasia fosters TME formation, angiogenesis, and metastasis, whereas cuproptosis may alleviate mitochondrial dysfunction and hypoxic conditions in the TME. Inhibiting cuproplasia and enhancing cuproptosis in HCC are essential for achieving therapeutic efficacy in HCC.

An in-depth analysis of cuproplasia and cuproptosis mechanisms within the TME of HCC unveils their opposing nature and their impact on copper regulation. Grasping the equilibrium between these two factors is crucial for a deeper understanding of HCC mechanisms to shed light on novel directions in treating HCC.

Lung cancer is a serious threat to human life and health, but effective screening and treatment methods are lacking. Circular RNAs (circRNAs) have important biological functions and are closely related to tumour development. Some studies have shown that the 8-oxo-7,8-dihydroguanosine (o8G) modification plays a key role in the disease process, but the effect of the o8G modification on circRNAs has not been elucidated. Moreover, cuproptosis is a novel mode of cell death in which copper ions directly promote protein aggregation and the disruption of cellular metabolic pathways. The present study revealed that the o8G modification of circKIAA1797 occurs and promotes lung cancer development by inhibiting cuproptosis, which provides new perspectives for epitranscriptomic studies and the development of novel therapeutic approaches for lung cancer.

circRNA differential expression profiles in lung cancer were revealed via RNA high-throughput sequencing, and circKIAA1797 expression in lung cancer cell lines and tissues was detected using qPCR. Experiments such as o8G RNA immunoprecipitation (o8G RIP) and crosslinking immunoprecipitation (CLIP) were performed to explore the presence of o8G on circKIAA1797. The regulation of circKIAA1797 by the o8G reader Y-box binding protein 1 (YBX1) was explored using nuclear-cytoplasmic fractionation, actinomycin D (Act D) stability experiments and other experiments. circKIAA1797 silencing and overexpression systems were constructed for in vivo and in vitro experiments to study the role of circKIAA1797 in lung cancer development. Tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP), and immunofluorescence (IF) staining were subsequently conducted to reveal the molecular mechanism by which circKIAA1797 regulates cuproptosis and promotes lung cancer development.

This study is the first to reveal the presence of o8G on circKIAA1797 and that YBX1 is a reader that recognises ROS-induced circKIAA1797 o8G modifications and increases the stability and cytoplasmic expression of circKIAA1797. circKIAA1797, which is associated with the tumour stage and prognosis, has been shown to significantly promote the biological function of lung cancer development both in vivo and in vitro. This study revealed that circKIAA1797 inhibits intracellular cuproptosis by binding to the ferredoxin 1 (FDX1) mRNA, decreasing FDX1 mRNA stability, inhibiting FDX1 expression, and binding to the signal transducer and activator of transcription 1 (STAT1) protein and inhibiting lipoyltransferase 1 (LIPT1) transcription; moreover, circKIAA1797 promotes the closure of the mitochondrial permeability transition pore (mPTP), inhibits cuproptosis, and ultimately promotes lung cancer development.

This study revealed the presence of the o8G modification in circKIAA1797, which plays an important role in the development of lung cancer. circKIAA1797 can inhibit cuproptosis by inhibiting key cuproptosis proteins and promoting mPTP closure, ultimately promoting the development of lung cancer. This study provides not only a new theoretical basis for an in-depth understanding of the molecular mechanisms of lung cancer development but also a potential target for lung cancer treatment.

Elesclomol (ES) is a promising anticancer compound that exerts its effects through multiple mechanisms. It acts as a copper (Cu(II)) ionophore, forming an ES-Cu complex within cancer cells and inducing a novel form of cell death called cuproptosis.

To provide an up-to-date review on elesclomol and its nano-formulations with a particular focus on cancer therapy.

Literature was collected by manually searching in Pubmed, and Google Scholar, clinicaltrials.gov through March 2025.

This review provides an overview of the discovery and development of the ES molecule, including its physicochemical properties. New insights into the intracellular interactions of ES with copper and the mechanisms of copper transportation are then explained. The recent clinical outcomes of ES in cancer therapy, both as a monotherapy and in combination with paclitaxel or carboplatin, are summarized. While the initial clinical trials showed promise, more studies are focusing on the preclinical investigations of the ES-Cu complex. Nanomedicine-based formulations have emerged as a strategy to enhance the intracellular delivery of ES as well as its therapeutic effects, with several ES-Cu nanomedicines currently under development. The recent nanoparticle delivery strategies of ES are discussed. This comprehensive review provides an up-to-date overview of the recent advancements in ES study, including its novel mechanism of action, clinical progress, and the potential of nanomedicine-based approaches to improve its therapeutic efficacy in cancer treatment.

Copper is an essential micronutrient that is a cofactor for various enzymes involved in multiple cellular processes. Melanoma patients have high serum copper levels, and elevated copper concentrations are found in melanoma tumors. Copper influences the activity of several melanoma-related proteins involved in cell survival, proliferation, pigmentation, angiogenesis, and metastasis. Targeting these processes with copper chelators has shown efficacy in reducing tumor growth and overcoming drug resistance. In contrast, excessive copper can also have detrimental effects when imported into melanoma cells. Multiple distinct cellular effects of copper overload, including the induction of different types of cell death, have been reported. Cuproptosis, a novel type of copper-dependent cell death, has been recently described and is associated with the metabolic phenotype. Melanoma cells can switch between glycolysis and oxidative phosphorylation, which are crucial for tumor growth and drug resistance. In this respect, metabolic plasticity might be exploited for the use of copper-delivery strategies, including repurposing of disulfiram, which is approved for the treatment of noncancer patients. In addition, the development of nanomedicines can improve the targeted delivery of copper to melanoma cells and enable the use of these drugs alone or in combination as copper has been shown to complement targeted therapy and immunotherapy in melanoma cells. However, further research is needed to explore the specific mechanisms of both copper restriction and excess copper-induced processes and determine effective biomarkers for predicting treatment sensitivity in melanoma patients. In this review, we discuss the dual role of copper in melanoma biology.

Lung adenocarcinoma (LUAD), the most common histotype of lung cancer, exhibits high heterogeneity due to molecular variations. Cuproptosis is a newly discovered type of cell death that is linked to copper metabolism and long non-coding RNAs (lncRNAs) may play a significant role in this process. We conducted a comprehensive analysis of lncRNA related to cuproptosis and identified a CRLscore to predict the prognosis and immune landscape for LUAD patients.

The LUAD patient cohort obtained from TCGA database was divided into training and validation sets. A range of statistical methods were employed to identify lncRNAs associated with cuproptosis. Multivariate Cox regression was then utilized to develop the CRLscore, which was further used to construct and evaluate a nomogram. Additionally, we investigated the biological functions, gene mutations, and immune landscape.

A CRLscore, comprising six cuproptosis-related lncRNAs, was developed to stratify patients into high- and low-risk groups. The CRLscore demonstrated its ability to independently predict prognosis in both the training set and the validation set. Utilizing the CRLscore, we constructed a nomogram that exhibited favorable predictive efficiency. Furthermore, the cuproptosis-related lncRNAs exhibited associations with important signaling pathways such as p53 signaling, MYC Targets V1, and G2M Checkpoint. Notably, the CRLscore displayed substantial differences in somatic mutations and immune landscape. Finally, qRT-PCR results showed the significant differential expression of five cuproptosis-related lncRNAs between LUAD and normal cells.

The CRLscore could serve as a potential prognostic indicator and may predict the response to immunotherapy in LUAD patients.

As a common malignancy, hepatocellular carcinoma (HCC) proliferation and metastasis could be promoted by ferroptosis and cuproptosis. In this study, we screened out the differentially expressed cuproptosis- and ferroptosis-related genes (CFRGs) and identified the 17 informative prognosis-associated genes. A CFRG scoring model was constructed based on the subtypes identified by consensus clustering analysis and principal component analysis (PCA). Furthermore, the immune profile, expression of immune checkpoint genes (ICGs) and drug susceptibility were also compared between the two CFRG score groups. The results showed that patients with a high CFRG score had higher survival probabilities. The correlation analysis suggested that CFRG scores were negatively correlated with activated CD4.T.cell. The expression patterns of thirty ICGs and the half-maximal inhibitory concentration (IC50) values of 128 drugs displayed significant differences between the two CFRG score groups. A statistically significant difference in the efficacy of sorafenib was found between the two CFRG score groups. Moreover, based on multivariate COX regression analysis and weighted gene co-expression network analysis (WGCNA), we screened DLAT and SLC2A1 as signature genes. Molecular docking analysis revealed that DLAT and SLC2A1 had a strong binding affinity toward camptothecin, rapamycin, dactolisib, and luminespib. The correlation between the CFRG score and single-cell characteristics was further explored. The study depended on our understanding of the biological function of CFRGs in HCC and provided new insights for developing treatment strategies.

The emergence of cuproptosis, a novel form of regulated cell death, is induced by an excess of copper ions and has been associated with the progression of multiple diseases, including liver injury, cardiovascular disease, and neurodegenerative disorders. However, there are currently no inhibitors available for targeting specific cuproptosis-related pathways in therapy. Here, the compound merestinib (MTB) has been identified as a strong inhibitor of cuproptosis through screening of a kinase inhibitor library. The results show that MTB effectively blocks elesclomol-CuCl2 (ES-Cu) induced cuproptosis by preventing the aggregation of lipoylated proteins and the destabilization of Fe-S cluster proteins, thereby preventing proteotoxic stress and ultimately cell death. Mechanistically, MTB decreases oxidative stress levels by binding directly to NRF2. Additionally, it boosts the efficiency of the copper homeostasis and facilitates the exocytosis and transportation of copper ions, ultimately inhibiting cuproptosis. Furthermore, our research showed that MTB has the ability to alleviate cuproptosis-driven acute liver injury in mice. These findings suggest that MTB is a specific inhibitor of cuproptosis, presenting a hopeful option for therapeutic approaches in cuproptosis-related diseases.

Cancer remains one of the leading causes of the death of individuals globally. Conventional treatment techniques like chemotherapy and radiation often suffer various drawbacks like toxicity and drug resistance. The study of cell death has been predominantly focused on classical forms like apoptosis, but the role of metal ions in governing controlled cell death is a fascinating and less explored area. Metal-mediated controlled cell death is a process where metal triggers cell death via a unique mechanism. Nanomaterial-based strategies have gained attention for their ability to deliver precise therapeutic agents while also triggering Regulated Cell Death (RCD) mechanisms in cancer cells. The recently discovered metal-mediated controlled cell death techniques like cuproptosis and ferroptosis can be used in cancer treatment as they can be used selectively for the treatment of drug-resistant cancer. Nano material-based delivery system can also be used for the precise delivery of the drug to the targeted sites. In this review, we have given some idea about the mechanism of metal-mediated controlled cell death techniques (ferroptosis and cuproptosis) and how we can initiate controlled cell deaths using nanomaterials for cancer treatment.

The cuproptosis is an intracellular copper (Cu) accumulation triggering the aggregation of mitochondrial lipoylated proteins and destabilization of iron‑sulfur (FeS) cluster proteins, leading to cell death. This copper-triggered modality of mitochondrial cell death has been associated with cuproptosis-related signature key genes (CRGs). Our study focused on the relationship between the cuproptosis CRGs and diabetic nephropathy (DN) to understand how such immune microenvironment may influence DN.

We downloaded and compared RNA sequencing data sets of DN glomerular tissue samples vs. normal renal tissue samples (GSE142025, GSE30528, and GSE96804) from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between DN and control samples were screened. Immune cell subtypes infiltration and immune score were figured out via different algorithms. Consensus clustering was performed by the Ward's method to determine different phenotypes of DN. CRG key genes between two phenotypes were identified via machine learning algorithm. Logistic regression analysis was applied to establish a nomogram for assessing the risk of DN.

In DN samples, two genes NLRP3 and CDKN2A were positively correlated to the immune score. In contrast, six genes NFE2L2, LIAS, LIPT1, DLD, DBT and DLST were negatively correlated to the immune score. Via Consensus clustering based on cuproptosis CRG key genes, the DN samples were divided into cluster C1 and cluster C2. The cluster C1 was characterized by low cuproptosis CRG genes expression, high immune cell subtypes infiltration, and high enrichment of immune-related pathways. Cluster C2 was on the contrary, the Dicarbonyl/l-xylulose reductase (DCXR) and heat-responsive protein 12 (HRSP12) genes were related to clinical traits and the immune microenvironment, negatively correlated with most immune cell subtypes. The nomogram was constructed based on DCXR and HRSP12 showing good efficiency for the DN diagnosis.

We conclude that the immune microenvironment imbalance and metabolic disorders lead to the occurrence of DN. The signature cuproptosis genes, regulating the immune microenvironment and metabolism, represented the DN disease clustering to describe the heterogeneity and characterize immune microenvironment. Both HRSP12 and DCXR key genes are related to DN disease phenotypes and immune microenvironment characteristic and may help in DN diagnosis.

Gliomas constitute the most prevalent primary central nervous system tumors, often characterized by complex metabolic profile, genomic instability, and aggressiveness, leading to frequent relapse and high mortality rates. Traditional treatments are commonly ineffective because of gliomas increased heterogeneity, invasive characteristics and resistance to chemotherapy. Among several pathways affecting cellular homeostasis, cuproptosis has recently emerged as a novel type of programmed cell death, triggered by accumulation of copper ions. Although the precise molecular mechanisms of cuproptosis are not fully elucidated, there is evidence that copper ions can target mitochondrial lipoylated proteins, disrupting the tricarboxylic acid cycle and electron transport chain, thus leading to deregulated mitochondrial metabolism, protein aggregation and cell death. Of importance, altered expression of copper transporters and abnormally high intracellular copper levels have been observed in several cancer types, including gliomas, contributing to tumor growth and metastasis. Furthermore, a range of prognostic models incorporating cuproptosis-related genes and lncRNAs have been proposed and are currently under clinical validation. Drugs modulating cuproptosis or interfering with copper-binding proteins are under development, causing metabolic failure and cell death, thus offering potential new avenues for glioma diagnosis and therapy. In this article, we explore the role of copper metabolism in gliomas and the potential synergistic effects of cuproptosis-based treatments with current therapies, in effective targeting of tumor progression and chemoresistance.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

Copper has emerged as a promising target for cancer therapy, with extensive studies on copper accumulation-induced cuproptosis. However, the potential of copper depletion-induced cuproptosis remains largely unexplored. Recently, Zhou et al. (M. Zhou, F. Muhammad, Y. Zhang, T. Li, J. Feng, J. Zhao and H. Wei, Chem. Sci., 2025, https://doi.org/10.1039/D4SC04712E) reported an innovative strategy for copper depletion-based cuproptosis. Notably, this approach leverages the solubility product principle, a mechanism not previously addressed in studies, to achieve effective tumor therapy through the disruption of copper homeostasis.

Cuproptosis exhibits enormous application prospects in treatment. However, cuproptosis-based therapy is impeded by the limited intracellular copper ions, the nonspecific delivery, uncontrollable release, and chelation of endogenous overproduced glutathione (GSH). In this work, an ultrasound-triggered nanosonosensitizer (p-TiO2-Cu(I)) was constructed for Cu(I) delivery, on-demand release, GSH consumption, and deeper tissue response. When the nanomedicine was internalized into the tumor cells, ultrasound (US) induced the nanosonosensitizer to produce reactive oxygen species (ROS) to achieve sonodynamic therapy (SDT). GSH, acting as a hole trapping agent, improved the efficiency of SDT. Meanwhile, the downgrade of GSH was beneficial to cuproptosis and oxidative damage-based SDT in return. What is more, the US could regulate the release behavior of Cu(I). Cu(I) bonded to mitochondrial proteins and then aggregated the lipoylated protein, bringing about the turbulence of the tricarboxylic acid cycle. The combination of SDT and cuproptosis showed high matching to induce efficient cuproptosis and may inspire other cuproptosis-based nanosonosensitizer designs.

While drug therapy and allergen immunotherapy are useful for alleviating symptoms of seasonal allergic rhinitis (AR), existing therapeutic options remain limited. Cuproptosis is a novel form of programmed cell death, and its role in allergic rhinitis has not yet been explored. Researching the interaction between cuproptosis and allergic rhinitis will likely pave the way for future treatment of this disease.

A microarray dataset of AR patients and normal controls (GSE43523) were obtained from the Gene Expression Omnibus (GEO) database for differential gene analysis. Cuproptosis related genes were extracted from the differentially expressed genes (DEGs) to form the AR/cuprotosis-gene set and analyzed by the GO and KEGG databases. Intersection analysis further defined the AR signature genes (AR-sg). Consensus cluster analyses were used to define the AR/cuprotosis-genes into subsets. Finally, AR signature genes were used as targets for drug prediction and molecular docking to identify candidate drugs that may affect SAR.

Four AR signature genes (MRPS30, CLPX, MRPL13, and MRPL53) were selected by the MCC, EPC, BottleNeck, and Closeness algorithms. Correlation analysis of the AR signature genes and immune genes showed strong interactions; xCell analysis identified multiple immune cell types and supported these cells' importance in the AR pathogenesis. Finally, drug target analysis suggests that 1,5-isoquinolinediol and gefitinib have the potential to become future AR treatments.

Our study analyzed allergic rhinitis and cuproptosis related genes by the bioinformatics approach and predicted 1,5-isoquinolinediol and gefitinib as potentially useful drugs for treating AR patients in the future.

Programmed Cell Death (PCD) processes have been suggested to play a role in the development of cancers. The study aimed to investigate the enrichment of different types of PCD and identify important PCD-related genes in Thyroid Carcinoma (THCA).

The whole study is based on transcriptomic analysis and Immunohistochemistry (IHC) experiments. For transcriptomic analysis, the transcriptomic data of THCA (n = 493) and normal thyroid samples (n = 58) was used. The enrichment score of different types of PCD in THCA samples was calculated and the most enriched PCD process was identified. Then the expression of PCD-related genes in control and THCA samples were compared and the association between cuproptosis and characteristics of Tumor Microenvironment (TME) in THCA tissues was explored. IHC experiment was performed to confirm gene expressions in THCA and para-tumor samples.

Enrichment analysis showed that cuproptosis was the most enriched type of PCD process and associated with malignancy in THCA. The expression of a cuproptosis-related gene, CDKN2A, was found and confirmed to be higher in THCA than normal samples and associated with poor outcomes and higher clinical stages of patients with THCA. Moreover, CDKN2A expression was associated with immunosuppressive TME in THCA.

Our findings indicated the important role of cuproptosis and a cuproptosis-related gene, CDKN2A, in the development and progression of THCA, which might provide novel insights into the understanding of pathophysiology of THCA.

As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.

Sonodynamic therapy (SDT) is a minimally invasive therapeutic approach that utilizes sonosensitizers to catalyze substrates and generate reactive oxygen species (ROS) under ultrasound stimulation, ultimately inducing tumor cell death. Enhancing the piezoelectric properties of nanomaterials and modulating the semiconductor energy band are effective strategies to improve the catalytic efficiency of sonosensitizers. In this study, we developed a two-dimensional (2D) copper-based piezoelectric metal-organic framework (MOF) sonosensitizer, denoted as CM, through the coordination of copper and dimethylimidazole. The unique 2D MOF structure imparts CM with piezoelectric characteristics, enabling it to enhance SDT efficacy by modulating the semiconductor bandgap and carrier mobility. Upon ultrasound irradiation, CM catalyzes oxygen to undergo a cascade reaction, producing highly toxic singlet oxygen. Additionally, cupric ions in CM can be reduced by glutathione, facilitating the spontaneous catalysis of hydrogen peroxide in tumors to generate hydroxyl radicals and deplete glutathione, thereby inducing oxidative damage. Moreover, cupric ions in CM can trigger tumor cell cuproptosis, which, in combination with the generated ROS, accelerates cell death. Thus, this study establishes a MOF-based system for controllably inducing multi-pathway cancer cell death and provides a foundation for enhancing ultrasound-catalyzed tumor therapy through the optimization of piezoelectric properties.

The translocation of proteins from the cytoplasm to the endoplasmic reticulum occurs via a conserved Sec61 protein channel. Previously, we reported that mutations in histones cause downregulation of a CUP1 copper metallothionein, and copper exposure inhibits the activity of Sec61. However, the role of epigenetic dysregulation on the activity of channel is not clear. Identification of cellular factors regulating copper metabolism and Sec61 activity is needed as the dysregulation can cause human diseases. In this study, we elucidate the intricate relationship between copper homeostasis and Sec61-mediated protein translocation. Utilizing copper-sensitive yeast histone mutants exhibiting deficiencies in the expression of CUP1, we uncover a copper-specific impairment of the protein translocation process, causing a reduction in the maturation of secretory proteins. Our findings highlight the inhibitory effect of copper on both cotranslational and posttranslational protein translocations. We demonstrate that supplementation with a copper-specific chelator or amino acids such as cysteine, histidine, and reduced glutathione, zinc, and overexpression of CUP1 restores the translocation process and growth. This study, for the first time provides a functional insight on epigenetic and metabolic regulation of copper homeostasis in governing Sec61-dependent protein translocation process and may be useful to understand human disorders of copper metabolism.

Copper, an essential trace element and biochemical cofactor in humans plays a critical role in maintaining health. Recent studies have identified a significant association between copper levels and the progression and metastasis of cancer. Copper is primarily absorbed in the intestinal tract, often leading to an imbalance of copper ions in the body. Colorectal cancer (CRC), the most common cancer originating in the intestines, thrives in an environment with elevated copper concentrations. Current research is focused on uncovering the relationship between copper and CRC which has introduced new concepts such as cuproplasia and cuproptosis, significantly deepening our understanding of copper's influence on cell proliferation and death. Cuproplasia is a kind of cell proliferation mediated by the co-regulatory activities of enzymes and non-enzymatic factors, while cuproptosis refers to cell death induced by excessive copper, which results in abnormal oligomerization of lipacylated proteins and the reduction of iron-sulfur cluster proteins. Exploring cuproplasia and cuproptosis opens new avenues for treating CRC. This review aims to summarize the critical role of copper in promoting colorectal cancer, the dual effects of copper in the tumor microenvironment (TME), and strategies for leveraging this unique microenvironment to induce cuproptosis in colorectal cancer. Understanding the relationship between copper and CRC holds promise for establishing a theoretical foundation for innovative therapeutic strategies in CRC.

Background/Objectives: Preclinical studies have shown that the anti-malarial drug hydroxychloroquine (HCQ) improves the anti-cancer effects of various therapeutic agents by impairing autophagy. These findings are difficult to translate in vivo as reaching an effective HCQ concentration at the tumor site for extended times is challenging. Previously, we found that free HCQ in combination with gefitinib (Iressa®, ZD1839) significantly reduced tumor volume in immunocompromised mice bearing gefitinib-resistant JIMT-1 breast cancer xenografts. Here, we sought to evaluate whether a liposomal formulation of HCQ could effectively modulate autophagy in vivo and augment treatment outcomes in the same tumor model. Methods: We developed two liposomal formulations of HCQ: a pH-loaded formulation and a formulation based on copper complexation. The pharmacokinetics of each formulation was evaluated in CD1 mice following intravenous administration. An efficacy study was performed in immunocompromised mice bearing established JIMT-1tumors. Autophagy markers in tumor tissue harvested after four weeks of treatment were assessed by Western blot. Results: The liposomal formulations engendered ~850-fold increases in total drug exposure over time relative to the free drug. Both liposomal and free HCQ in combination with gefitinib provided comparable therapeutic benefits (p > 0.05). An analysis of JIMT-1 tumor tissue indicated that the liposomal HCQ and gefitinib combination augmented the inhibition of autophagy in vivo compared to the free HCQ and gefitinib combination as demonstrated by increased LC3-II and p62/SQSTM1 (p62) protein levels. Conclusions: The results suggest that liposomal HCQ has a greater potential to modulate autophagy in vivo compared to free HCQ; however, this did not translate to better therapeutic effects when used in combination with gefitinib to treat a gefitinib-resistant tumor model.

The efficacy of sonodynamic therapy (SDT), an emerging approach for tumor treatment, is hindered by the high levels of the antioxidant glutathione (GSH) in the tumor microenvironment (TME). In this study, we constructed nanobubbles loaded with the sonosensitizer HMME and the tumor-targeting peptide RGD (HMME-RGD@C3F8 NBs) for synergistic SDT/cuproptosis therapy of liver hepatocellular carcinoma (LIHC) in combination with Elesclomol-Cu as cuproptosis inducers. Endogenous GSH is consumed by Cu2+ to modulate the complex TME, thereby amplifying oxidative stress and further improving SDT performance. Additionally, intracellular Cu2+ overload can induce cuproptosis, which is further amplified by SDT, to initiate irreversible protein toxicity. The specific mechanism of synergistic SDT/cuproptosis therapy in LIHC was investigated by RNA sequencing analysis. The synergistic SDT/cuproptosis therapy reprogrammed the TME to improve the efficacy of immune checkpoint inhibitor-based immunotherapy. Furthermore, a risk-scoring model was created and displayed significant promise in the prognosis of LIHC.

Renal fibrosis is a common final pathway underlying nearly almost all progressive kidney diseases. Metal ions are essential trace elements in organisms and are involved in important physiological activities. However, aberrations in intracellular metal ion metabolism may disrupt homeostasis, causing cell death and increasing susceptibility to various diseases. Accumulating evidence suggests a complex association between metal-dependent cell death and renal fibrosis. In this article, we provide a comprehensive overview of the specific molecular mechanisms of metal-dependent cell death and their crosstalk, up-to-date evidence supporting their role in renal fibrosis, therapeutic targeting strategies, and research needs, aiming to offer a rationale for future clinical treatment of renal fibrosis.

Cuproptosis is a regulated form of cell death induced by the accumulation of metal ions and is closely linked to aspects of cellular drug resistance, cellular metabolism, and signalling pathways. Due to its crucial role in regulating physiological and pathological processes, cuproptosis has gained increasing significance as a potential target for anticancer drug development. In this review, we introduce the definition of cuproptosis and provide a comprehensive discussion of the mechanisms of cuproptosis. In addition, the methods for the detection of cuproptosis are summarized, and recent advances in cuproptosis in cancer therapy are reviewed, mainly in terms of elesclomol (ES)-mediated cuproptosis and disulfiram (DSF)-mediated cuproptosis, which provided practical value for applications. Finally, the current challenges and future development of cuproptosis-mediated cancer therapy are discussed. In summary, this review highlights recent progress on cuproptosis in cancer therapy, offering novel ideas and strategies for future research and applications.

This study investigated the regulatory effect of LncRNA-GAS5 on FDX-1 in HEK293T cells by Acinetobacter baumannii. Transfected LncRNA-GAS5 overexpressing or knocking down plasmids into HEK293T cells, and the expression of FDX-1 was detected by Western blotting. A. baumannii inhibited the expression of FDX-1. Overexpression of LncRNA-GAS5 inhibited the expression of FDX-1, while knocking down LncRNA-GAS5 increased the expression of FDX-1. Overexpression of LncRNA-GAS5 further enhanced the inhibitory effect of A. baumannii on FDX-1, while knocking down LncRNA-GAS5 restored the inhibitory effect of A. baumannii on FDX-1. LncRNA-GAS5 regulates the inhibitory effect of A. baumannii on FDX-1 in HEK293T cells.

Nature often provides invaluable insights into technological innovation and the construction of nanomaterials. Inspired by the pitaya fruit's strategy of wrapping seeds within its pulp to enhance seed survival, a unique nanocomposite based on metal-organic framework (MOF)-encapsulated CuS nanoparticles (NPs) is developed. This design effectively addresses the challenge of short retention time afforded by CuS NPs for therapeutic and imaging purposes. The MOF acts as the "pitaya pulp" protecting the internal CuS NPs ("pitaya seeds"), thereby increasing their retention time in vivo. This system exhibits triple-enzyme-mimicking activities and is proposed for application in photoacoustic and magnetic resonance imaging-guided therapies, including chemodynamic therapy, photothermal therapy, and cuproptosis-related therapy. The exceptional enzyme-mimicking activities of superoxide dismutase, catalase, and peroxidase not only produce oxygen to alleviate hypoxia but also generate a reactive oxygen species (ROS) storm for effective tumor destruction. By combining these multienzymatic properties, superior photothermal performance, and Cu-induced cuproptosis, nanozyme-treated mice exhibited an 84% inhibition of tumor growth-approximately double the effect observed in mice treated with CuS NPs alone. This study presents a smart strategy for integrating imaging with therapeutic modalities, achieving exceptional outcomes for precise imaging-guided tumor therapy.

Gastric cancer (GC) is a common digestive system cancer, characterized by a significant mortality rate. Mitochondria is an indispensable organelle in eukaryotic cells. It was previously revealed that a series of nucleus-encoded mitochondrial genes (NMG) mutations and dysfunctions potentially contribute to the initiation and progression of GC. However, the correlation between NMG mutations and survival outcomes for GC patients is still unclear. In this study, NMG expression profile and clinical information in GC samples were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Through consistent clustering and functional enrichment analysis, we have identified three NMG clusters and three gene clusters that are associated with patterns of immune cell infiltration. Prognostic genes were identified through Univariate Cox regression analysis. The principal component analysis was conducted to set up a scoring system. Subsequently, the Single‑cell RNA sequencing (scRNA-seq) data of GC patients and cancer cell drug sensitivity data were retrieved from the GEO database. Patients with high NMG scores exhibited increased microsatellite instability status and a heightened tumor mutation rate compared to those with low NMG scores. Survival analysis revealed that GC samples with high NMG scores could achieve a better prognosis. Additionally, These patients were observed to be more responsive to immunotherapy. Moreover, we delved into prognostic genes at the level of single cells, revealing that MRPL4 and MRPL37 exhibit high expression in epithelial cells, while TPM1 demonstrates high expression in tissue stem cells. Utilizing cancer cell drug sensitivity data from the Drug Sensitivity in Cancer (GDSC) database, we noted a heightened sensitivity to chemotherapy in the high NMG group. Furthermore, we discovered a significant enrichment of cuproptosis-related genes in clusters with high NMG scores. Consequently, employing the scoring system could facilitate the prediction of GC patients' sensitivity to cuproptosis-induced therapy. Our study confirmed the potency of this scoring system as a therapeutic response biomarker for gastric cancer, potentially informing clinical treatment strategies.

Cancer, a pressing global health challenge, is characterized by its rapid onset and high mortality rates. Conventional treatment methods prove insufficient in achieving the desired therapeutic outcomes, underscoring the critical need to identify an effective and safe approach for cancer treatment. In this study, a copper-doped nanoparticle known as Cu2+-DOX@ZIF-90 is designed by incorporating copper(II) (Cu(II)) and encapsulating doxorubicin (DOX) within ZIF-90. Leveraging the elevated ATP levels in cancer cells relative to normal cells, Cu2+-DOX@ZIF-90 undergoes intracellular degradation, leading to the release of DOX and Cu(II). DOX, a traditional chemotherapy drug for clinical use, induces apoptosis in cancer cells. Cu(II) interacts with glutathione (GSH) to generate Cu(I), catalyzing H2O2 to produce ˙OH, thereby prompting apoptosis in cancer cells. Concurrently, the reduction of GSH enhances the therapeutic effect of chemodynamic therapy (CDT). Furthermore, Cu(II) triggers the aggregation of lipoylated mitochondrial proteins, leading to the formation of DLAT oligomers and ultimately promoting cuproptosis in cancer cells. In vivo experimental findings demonstrate that Cu2+-DOX@ZIF-90 does not cause damage to normal tissues and organs in tumor-bearing mice, with a notable tumor inhibition rate of 86.18%. This synergistic approach, combining chemotherapy, CDT, and cuproptosis, holds significant promise for the effective and safe treatment of cancer.

The development, progression, and curative efficacy of head and neck squamous cell carcinoma (HNSCC) are influenced by complex interactions between epithelial and immune cells. Nevertheless, the specific changes in the nature of these interactions and their underlying molecular mechanisms in HNSCC are not yet fully understood. Cuproptosis, a form of programmed cell death that is dependent on copper, has been implicated in cancer pathogenesis. However, the understanding of cuproptosis in the context of HNSCC remains limited. In this study, we have discovered that cuproptosis-related long non-coding RNAs (CRLs) known as JPX play a role in promoting the expression of the oncogene urokinase-type plasminogen activator (PLAU) by competitively binding to miR-193b-3p in HNSCC. The increased activity of the JPX/miR-193b-3p/PLAU axis in malignant epithelial cells leads to enhanced cell proliferation, migration, and invasion in HNSCC. Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial-immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial-immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.

Herein, a ccRCC targeting nanodrug is designed to enhance chemodynamic therapy (CDT) as well as activate cuproptosis and tumor immunotherapy via ccRCC cell membrane modifying CuO@Gd2O3 yolk-like particles (CGYL) loaded with lactate oxidase (LOx) (mCGYL-LOx). Benefiting from the homologous targeting effect of Renca cell membranes, the mCGYS-LOx can be effectively internalized by Renca cells, open the "gate", and then release LOx and copper (Cu) ions. LOx can catalyze excessive lactate in Renca cells into H2O2, following that the produced H2O2 is further converted by Cu ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive Cu ions effectively trigger tumor cuproptosis. These synergistic effects induce the release of damage associated molecular patterns (DAMPs) and activate immunogenic cell death (ICD), leading to DC maturation and infiltration of immune effector cells. Moreover, LOx-mediated lactate consumption downregulates the expression of PD-L1, crippling tumor immune escape. In addition, the mCGYL-LOx improves T1-weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrates that the mCGYL-LOx has great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy.

Copper, a vital micronutrient, performs essential functions in numerous biological settings. Its disrupted metabolism is implicated in both the initiation of tumors and therapeutic interventions for cancer, underscoring the critical necessity of preserving copper homeostasis. Cuproptosis, a regulated cell death (RCD) modulated by copper, is activated in response to elevated copper concentrations, prompting an investigation into its implication in oncogenesis. Within this review, an exploration is conducted into copper dynamics and homeostasis maintenance within cells. Furthermore, it delves into the mechanisms underlying cuproptosis and its interplay with signaling pathways implicated in cancer. The potential synergy between cuproptosis and ferroptosis and its impact on tumor immunomodulation is discussed. Additionally, promising avenues for addressing cuproptosis in cancer involve assessing the utility of copper chelators and ionophores. By addressing pressing questions surrounding cuproptosis and outlining its pivotal role in cancer pathogenesis and treatment, this review propounds targeting cuproptosis as a promising frontier in antitumor therapy, potentially revolutionizing cancer treatment strategies.

Bladder cancer is the most common malignancy of the urinary tract and one of the most common cancers in the world. Cuproptosis is a novel type of cell death associated with tumorigenesis. In this study, we assessed the correlation between cuproptosis-related genes and tumorigenesis. Moreover, we constructed a prognostic signature.

Pearson correlation analysis and univariate Cox regression were utilized to extract cuproptosis-related long non-coding RNAs (lncRNAs) predicting prognosis in The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression was utilized to establish a cuproptosizs-related prognostic signature. A nomogram signature was generated to predict individual survival.

We obtained 19 cuproptosis-related genes and 14 prognostic cuproptosis-related lncRNAs. We constructed a seven-prognostic risk signature. Time-dependent receiver operating characteristic (ROC) curves demonstrated good predictive power (1-, 3-, and 5-year survival rates of 0.711, 0.673, and 0.684, respectively). The high-risk group reported a worse prognosis than the low-risk group, and the risk signature was identified as an independent factor. The biological process of risk-related genes primarily involved tumorigenesis and migration. The high-risk group expressed high chemokines and T cell inhibition and low antigen-presenting cells.

Cuproptosis-related lncRNAs are central to tumorigenesis, providing a novel therapeutic target for patients with bladder cancer. We constructed an individualized predictive signature based on cuproptosis-related lncRNAs.

Copper is crucial for many physiological processes across mammalian cells, including energy metabolism, neurotransmitter synthesis, and antioxidant defense mechanisms. However, excessive copper levels can lead to cellular toxicity and "cuproptosis", a form of programmed cell death characterized by the accumulation of copper within mitochondria. Tumor cells are less sensitive to this toxicity than normal cells, the mechanism for which remains unclear. We address this important issue by exploring the role of heat shock factor 1 (HSF1), a transcription factor that is highly expressed across several types of cancer and has a crucial role in tumor survival, in protecting against copper-mediated cytotoxicity. Using pancreatic ductal adenocarcinoma cells, we show that excessive copper triggers a proteotoxic stress response (PSR), activating HSF1 and that overexpressing HSF1 diminishes intracellular copper accumulation and prevents excessive copper-induced cell death and amyloid fibrils formation, highlighting HSF1's role in preserving proteasomal integrity. Copper treatment decreases the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), an enzyme necessary for cuproptosis, induces DLAT oligomerization, and induces insoluble DLAT formation, which is suppressed by overexpressing HSF1, in addition to enhancing the interaction between HSF1 and DLAT. Our findings uncover how HSF1 protects against copper-induced damage in cancer cells and thus represents a novel therapeutic target for enhancing copper-mediated cancer cell death.

Tumor cell death induced by "cuproptosis" is a novel form of tumor death that differs from apoptosis induced by chemotherapy. It is expected to emerge as a new approach for cancer treatment. In this study, our focus was on exploiting the characteristic of "cuproptosis" which necessitates increased aerobic respiration to induce tumor cell death. To achieve this, we developed a novel drug delivery system using a CaCO3@CuO2 lipid coating (CaCO3@CuO2@L). This system aimed to comprehensively modulate the tumor microenvironment and trigger "cuproptosis" in hepatocellular carcinoma (HCC) through the interaction between copper ions and peroxides. Experimental results revealed that the CaCO3@CuO2@L exhibited a distinct watermelon shape, with CuO2 evenly distributed within the CaCO3 nanoparticles. The nanoparticles had an average size of approximately 191 nm. In vitro studies demonstrated that the nanoparticles released CuO2 in a slightly acidic environment while simultaneously elevating pH levels, reducing glutathione (GSH), and increasing oxygen production. Within liver cancer cells, the CaCO3@CuO2@L effectively regulated the acidity, GSH levels, and oxygen-depleted microenvironment through the "trinity" mechanism, ultimately inducing "cuproptosis" in HCC. Furthermore, in mouse models with transplanted tumors and orthotopic liver cancer tumors, the CaCO3@CuO2@L significantly suppressed tumor growth. By triggering "cuproptosis" in HCC, this study offers valuable insights for developing a comprehensive treatment approach for HCC. Ultimately, this research may pave the way for the clinical implementation of the drug delivery system based on "cuproptosis" in liver cancer treatment.