PeerJ
·
2024
·
IF 2.3
Bingyu Wang,Jianqing Zhou,Ning An
Cuproptosis-related key genes play a significant role in the pathological processes of acute myocardial infarction (AMI). However, a complete understanding of the molecular mechanisms behind this participation remains elusive. This study was designed to identify genes and immune cells critical to AMI pathogenesis. Based on the GSE48060 dataset (31 AMI patients and 21 healthy persons, GPL570-55999), we identified genes associated with dysregulated cuproptosis and the activation of immune responses between normal subjects and patients with a first myocardial attack. Two molecular clusters associated with cuproptosis were defined in patients with AMI. Immune infiltration analysis showed that there was significant immunity heterogeneity among different clusters. Multiple immune responses were closely associated with Cluster2-specific differentially expressed genes (DEGs). The generalized linear model machine model presented the best discriminative performance with relatively lower residual and root mean square error, and a higher area under the curve (AUC = 0.870). A final two-gene-based generalized linear model was constructed, exhibiting satisfactory performance in two external validation datasets (AUC = 0.719, GSE66360 and AUC = 0.856, GSE123342). Column graph, calibration curve, and decision curve analyses also proved the accuracy of AMI prediction. We also constructed a mouse C57BL/6 model of AMI (3 h, 48 h, and 1 week) and used qRT-PCR and immunofluorescence to detect the expression changes of CBLB and ZNF302. In this study, we present a systematic analysis of the complex relationship between cuproptosis and a first AMI attack, and provide new insights into the diagnosis and treatment of AMI.
研究领域:
生物信息学
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医学
·
心血管疾病
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Junmin Qian,Abdalrheem Jarelnaby Musa Aldai,Weijun Xu,Taibing Wang,Kunkun Zhao,Yaping Wang,Jingjing Fan,Aili Suo
Cuproptosis shows great prospects in cancer treatments. However, insufficient intracellular copper amount, low-level redox homeostasis, and hypoxic tumor microenvironment severely restrict cuproptosis efficacy. Herein, hydrazided hyaluronan-templated decorated CuO 2 -doxorubicin (CuDT) nanodot clusters (NCs) are developed for efficient doxorubicin (DOX)-sensitized cuproptosis therapy in breast cancer via a three-pronged strategy. The CuDT NCs with an average size of 56.2 nm are fabricated from 3,3′-dithiobis(propionohydrazide)-conjugated hyaluronan, Cu 2+ , and DOX through a one-pot mineralization process. The CuDT nanoparticles exhibit pH-responsive H 2 O 2 , Cu 2+ , and DOX release profiles and catalytic activity. Upon entrance into tumor cells, CuO 2 -based exogenous H 2 O 2 supply and DOX-augmented endogenous H 2 O 2 generation jointly elevate intracellular H 2 O 2 level, which can further be transformed into hydroxyl radicals and O 2 through Fenton-like reaction to achieve oxidative stress amplification and hypoxia relief, respectively. Moreover, the CuDT NCs can efficiently deplete intracellular overexpressed glutathione via Cu 2+ /Cu + cycle and abundant disulfide bonds, further enhancing cellular oxidative stress. These results demonstrate that the novel CuDT NCs achieve DOX-sensitized cuproptosis in breast cancer cells through elevating copper level, amplifying oxidative stress and alleviating hypoxia, and display prominent in vivo antitumor efficacy. Such a three-pronged strategy of targetedly boosting cuproptosis in cancer cells represents a novel approach for antitumor treatments.
研究领域:
肿瘤学
·
药理学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 33
·6296-6306
·
IF 7.571
Yao Lu,Qingqing Pan,Wenxia Gao,Yuji Pu,Bin He
Platinum-based chemotherapy is widely used to treat various cancers. However, exogenous platinum is likely to cause severe side effects and drug resistance induced by upregulated glutathione (GSH) in cancer cells poses a threat to the management of cancer progression and recurrence. Anticancer copper–organic complexes are excellent candidates to substitute platinum-based chemotherapeutics, exhibiting lower systemic toxicity and even overcoming platinum-based chemotherapy resistance. Here, we report the GSH-resistance of copper(II) bis(diethyldithiocarbamate) (CuET) and its reversal of cisplatin resistance in non-small-cell lung cancer via cuproptosis. Electrochemistry and UV-vis spectroscopy studies demonstrate that CuET possesses a lower reduction potential and the reaction inertness with GSH. Importantly, CuET overcomes the drug resistance of A549/DDP cells and the anticancer effect is hardly affected by intracellular GSH levels. To improve the solubility and bioavailability, bovine serum albumin-stabilized CuET nanoparticles (NPs) are prepared and they have a high drug loading content of 27.5% and excellent physiological stability. In vitro studies manifest that CuET NPs augment the distributions in the cytosol and cytoskeleton, inducing cell death via cuproptosis in A549/DDP cells, which is distinctly different from the apoptosis pattern induced by cisplatin. In vivo antitumor evaluation shows that the nanomedicine has superior biosafety and potent antitumor activity in a cisplatin-resistant tumor model. Our study suggests that copper–organic complex-based nanosystems could be a powerful toolbox to tackle the platinum-based drug resistance and systemic toxicity concerns.
研究领域:
肿瘤学
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药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Zhen Guo,Renlu Han,Yun Gao,Jie Fu,Zekai Zhuang,Yafei Hou,Jiancheng Yu,Keqi Tang
Abnormal metabolic symbiosis is one of the most typical features of tumors that distinguishes them from normal tissues. Disrupting tumor metabolic symbiosis has been recognized a promising tumor therapeutic approach. However, a single pathway intervention strategy greatly impedes its treatment efficiency. Herein, α-cyano-4-hydroxycinnamic acid (CHCA) and elesclomol (ES) co-loaded Cu 7 S 4 nanoplatform (named as CCE) is developed to synchronously intervene tricarboxylic acid (TCA) cycle and lactic acid metabolism through self-enhanced cuproptosis and acidosis for tumor metabolic symbiosis destruction. CCE could be triggered by up-regulated glutathione (GSH) in cancer cells to release ES, CHCA, Cu ions, and S 2− ions. On the one hand, ES significantly improves the influx efficiency of Cu ions to mitochondria where cuproptosis is initiated and TCA cycle is attacked. Meanwhile, the H 2 S produced by the binding of S 2− to H + in acidic tumor cells could induce mitochondrial damage and inhibit Cu ions efflux by depriving energy supply. Moreover, the GSH consumption reduces its chelation with Cu ions. Collectively, the increased intracellular Cu ions level significantly boosts cuproptosis mediated proteotoxicity of TCA cycle, thus aggravating TCA cycle injury. On the other hand, CHCA down-regulates the expression of monocarboxylate transporters 4 (MCT4) and inhibits lactic acid transport between tumor cells, causing the tumor cytoplasm acidification. Interestingly, H 2 S accelerates lactate production by promoting the glucose uptake to further potent the lactate metabolic disorder. In vitro and in vivo experiments confirm anti-tumor efficacy and biosafety of CCE. This study further enriches tumor therapeutic strategy.
研究领域:
肿瘤生物学
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代谢调控
·
生物化学
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Wenqi Wang,Yuyu Cui,Xiaolong Wei,Ying Zang,Xulin Chen,Liang Cheng,Xianwen Wang
Nanozyme-driven catalytic therapy provides a promising treatment strategy for bacterial biofilm-infected wounds. However, the single functionality and limited catalytic efficiency of nanozyme-based materials often restrict the effectiveness of wound infection treatment. In this study, CuCo2O4 nanoflowers with multiple enzymatic activities were prepared for antibacterial/antibiofilm treatment by cuproptosis-like death. CuCo2O4 exhibited peroxidase-like (POD-like) and oxidase-like (OXD-like) dual enzyme activities that generated large amounts of •OH and O2•–. Moreover, the glutathione peroxidase-like (GSH-Px-like) activity of CuCo2O4 was able to reduce the overexpression of GSH in the wound microenvironment, enhancing the therapeutic effects of reactive oxygen species (ROS). The morphology of CuCo2O4 was modified using a hydrothermal method with PEG4000 as the solvent, resulting in the exposure of more active center sites and a significant improvement in enzyme catalytic activity. The in vitro results demonstrated the pronounced disruption effect of CuCo2O4 on biofilms formed by bacteria. In vivo, CuCo2O4 significantly promoted angiogenesis, collagen deposition, and cell proliferation. Transcriptome sequencing revealed that elevated ROS levels in bacteria led to cell membrane damage and metabolic disruption. In addition, Cu2+ overload in bacteria induces lipid peroxidation accumulation and disrupts the respiratory chain and tricarboxylic acid (TCA) cycle, ultimately leading to bacterial cuproptosis-like death. This therapeutic strategy, which combines the synergistic effects of multiple enzyme-like activities with cuproptosis-like death, provides an approach for treating biofilm infections.
研究领域:
生物医学工程
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材料科学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Qingdong Li,Yuanyuan Cui,Zhenhong Xia,Wenjuan Gao,Jianmin Xiao,Zhen Zhao,Lei Yang,Guilong Zhang,Zhengyan Wu
Immunotherapy has emerged as a promising approach for melanoma treatment. However, the efficacy of traditional immune checkpoint inhibitors (ICIs) remains limited due to the immunosuppressive tumor microenvironment. In this study, a novel nano-immune agonist, pLCGM-OVA, was developed to induce cuproptosis and activate the cGAS-STING pathway, thereby enhancing melanoma immunotherapy. The pLCGM-OVA was synthesized by conjugating PDGFB with liposomes that encapsulate CuGdMn nanoclusters (CGM) and ovalbumin (OVA). Upon exposure to the acidic microenvironment of tumours, pLCGM-OVA undergoes degradation, releasing Cu ions, Mn ions, and free OVA. This release triggers reactive oxygen species-mediated cuproptosis and activates the cGAS-STING pathway via Mn, leading to the subsequent induction of immunogenic cell death (ICD). Simultaneously, free OVA and ICD antigens are presented to dendritic cells (DCs), promoting their maturation and enhancing cytotoxic T lymphocyte infiltration, thus improving the efficacy of tumour immunotherapy. In vitro and in vivo studies demonstrated that pLCGM-OVA significantly inhibited tumour growth and recurrence with minimal systemic toxicity, owing to the combined effects of cuproptosis and immunotherapy. Moreover, pLCGM-OVA exhibited excellent T 1 contrast (9.26 mM −1 s −1 ), significantly enhancing T 1 -weighted magnetic resonance imaging signals of tumours, facilitating accurate melanoma diagnosis. Overall, this work presents a highly promising candidate for the development of potent immune agonists for melanoma treatment.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Huiqun Hu,Shiyuan Hua,Feng Lu,Wenting Zhang,Zengwen Zhang,Jiarong Cui,Xiaoyue Lei,Jingyan Xia,Feng Xu,Min Zhou
The emergence of antibiotic-resistant bacteria has exacerbated the challenge of treating infectious diseases. Quorum sensing (QS), a bacterial communication system regulating virulence and biofilm formation, presents a target for novel therapies. Cuproptosis death is a innovation mode of death, however, this effect may be partially inhibited by glutathione (GSH). Buthionine sulfoximine (BSO) is responsible for GSH biosynthesis and has been identified as a potential promoter of cuproptosis death. Here, Cu 2 O-BSO NPs with lung adhesion and mucus penetration ability are synthesized by incorporating BSO onto Cu 2 O, and modifying it with DOPA and PEG. Cu 2 O-BSO NPs demonstrated a broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria, making it a viable treatment option for MRSA-induced acute pneumonia. Specifically, Cu 2 O-BSO NPs can synergistically enhance bacterial cuproptosis-like death, hinder the QS system, eradicate biofilms, reduce the virulence of strains, stimulate the chemotaxis and phagocytosis of macrophages, and ultimately improve in mice with severe pneumonia. This research demonstrated the potential of Cu 2 O-BSO NPs for a wide-ranging antibacterial alternative, providing promise for addressing microbial resistance and combatting biofilm formation. Additionally, it established a target and theoretical foundation for the clinical treatment of numerous challenging cases of acute drug-resistant bacteria.
研究领域:
医学
·
微生物学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Wei Chen,Chen Lin,Zhimin Gao,Yongxin Huang,Xinyi Wang,Qian Zhang,Yaru Zhang,Meiling Tan,Zhiyao Hou
Copper (Cu) ions are essential for inducing cuproptosis to inhibit tumor growth, and the therapeutic efficacy is limited by the chelation of over-expressed glutathione (GSH) and the efflux mechanisms of copper transporter proteins. Moreover, the hypoxic characteristic of the tumor microenvironment (TME) can impede the formation of lipoylated proteins in the tricarboxylic acid (TCA) cycle, thereby diminishing cuproptosis. Herein, Cu 2 O was served as active nano-carrier for delivering copper, followed by coating with cerium-based node metal-organic frameworks (Ce-MOFs) in situ on the surface to form core-shell structure Cu 2 O@Ce-MOFs (CM). Subsequently, the small molecule glucose transporter (GLUT) inhibitor KL-11743 was loaded onto CM to construct Cu 2 O@Ce-MOFs/KL-11743 (CMK) nanocomposites, achieving efficient cuproptosis for tumor treatment. The results show that CMK regulated the redox metabolism of the tumor microenvironment (TME) through glutathione oxidase (GSHOx) and peroxidase (POD) activities, significantly consuming excessive GSH and preventing copper ions from being chelated. Furthermore, KL-11743 released in response to TME inhibited the transport of glucose into cells via GLUT, resulting in a reduction of ATP synthesis and down-regulation of ATP7B expression, thereby achieving the restriction of copper ion efflux by regulating energy metabolism. The catalase (CAT) activity of CMK catalyzed the overexpressed H 2 O 2 in TME to generate O 2 , which entered the TCA cycle to promote lipoylated proteins oligomerization for sensitizing cuproptosis. Summary, CMK nanocomposites increased the effective Cu ions concentration within tumor cells by regulating metabolism, resulting in toxicity stress by hypoxia reversion induced efficient cuproptosis, which provides a potential strategy for clinical tumor treatment. Statement of significance This study addresses the challenge of insufficient effective copper ions and hypoxia in inhibiting cuproptosis by constructing TME-responsive Cu₂O@Ce-MOFs/KL-11743 (CMK) nanocomposites. In this design, CMK enhances intracellular copper retention through dual mechanisms: (1) redox metabolic regulation-mediated GSH depletion to inhibit copper ion chelation, and (2) KL-11743-targeted suppression of copper efflux via energy metabolic pathway inhibition. Concurrently, the enzyme-mimic activity of CMK catalyzes overexpressed H₂O₂ in the TME into O₂, alleviating hypoxia to promote lipoylated protein oligomerization. The synergistic integration of metabolic modulation and hypoxia reversal enables robust cuproptosis induction, establishing a reliable and clinically viable strategy for tumor treatment.
研究领域:
生物医学
·
肿瘤学
·
材料科学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2024
·
IF 5.8
Jingjing Jiang,Qiong Zhang,Yue Zhang,Lintong Gao,Yan Feng,Xianshun Sun,Junjun Wang,Xiao-Jiao Zhu,Xingxing Chen,Hong-Ping Zhou
Currently, cuproptosis mainly focuses on the Cu2+ induced morphology of mitochondria (Mito), the observation of endoplasmic reticulum (ER)-related Cu2+ content in cuproptosis is relatively lacking. Herein, we develop a hydroxyflavone (HF) based NIR excited fluorescent probe, BHCO, for exhibiting specific recognition of Cu2+. BHCO can accurately locate in ER and detect Cu2+ content in cuproptosis process. The two-photon fluorescence nature of BHCO enables to track both ferroptosis and cuproptosis processes with high resolution. Furthermore, BHCO can upgrade reactive oxygen species (ROS) under 720 nm excitation, which facilitates ferroptosis occurrence. We firmly convince the nonlinear optical (NLO) small molecules could provide a valid tool for rapid tumors elimination through synergistic ferroptosis and cuproptosis.
研究领域:
生物化学
·
肿瘤学
·
光学成像
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Yun Gao,Renlu Han,Zhen Guo,Zekai Zhuang,Jie Fu,Yafei Hou,Jiancheng Yu,Keqi Tang
Cuproptosis is a currently discovered programmed cell death modality driven by copper (Cu) ions, which shows potential application prospects in overcoming apoptotic resistance in cancer therapy due to its unique mechanism. Nevertheless, the efficiency of cuproptosis is restricted by strict Cu metabolism regulation. Herein, elesclomol (ES) and glucose oxidase (GOx) co-loaded CuFe 2 O 4 (CF) nanoplatform (termed as CFEG) was elaborately engineered to boost cuproptosis through multi-pathway copper metabolisms regulation. After triggered by tumor-overexpressed glutathione (GSH), the released ES continuously chelated and targeted transport Cu ions through a shuttle mechanism to mitochondria where cuproptosis was initiated, which dramatically improved the influx efficiency of Cu. Additionally, GOx-mediated glucose oxidation reaction together with Cu and Fe ions stimulated Fenton reaction simultaneously amplified intracellular oxidative pressure by hydrogen peroxide (H 2 O 2 ) self-supply and subsequent hydroxyl radical (•OH) generation, which down-regulated Cu exporter ATP7A expression and inhibited Cu ions efflux, thereby exacerbating cuproptosis. Furthermore, the consumption of GSH simultaneously reduced the chelation of GSH with Cu and promote the •OH generation, further potentiating the occurrence of cuproptosis. Collectively, such the multi-pathway copper metabolisms regulation including improved Cu influx, inhibited Cu efflux and GSH depletion significantly boosted cuproptosis, which synergized with photothermal effect of CF to efficiently repressed the growth of tumor in mice without causing systemic toxicity. This work provides a multivariate mode for enhanced tumor cuproptosis therapy, and may also inspire the design of advanced cuproptosis-related nanomedicine system.
研究领域:
生物医学工程
·
癌症治疗
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Yanan Fu,Huisong Hao,Yixuan Fang,Shengjie Sun,Simin Wen,Yuanqi Liu,Jia Tang,Tianqi Wang,Meiying Wu
The traditional copper ion carrier, elesclomol, relies on transporting extracellular copper ions into cells. However, the limited extracellular copper ions hinder the copper accumulation inside cells, limiting the cuproptosis effects and thus reducing its therapeutic efficacy in cancer treatment. Although metal peroxides are effective in transporting metals and inducing oxidative stress, their application is constrained by poor safety. To address these challenges, we develop a safe bicelle nanosystem for metal peroxide delivery. Typically, the assembly of lipid-based nanoparticles into non-spherical shapes requires stabilizing agents such as membrane-stabilizing proteins (MSPs). In this study, the hydrophobic effect within the bicelle cavities is leveraged to encapsulate copper peroxide (CP), ensuring efficient delivery. CP forms a stabilizing ring around the bicelle, mimicking the function of MSPs to reinforce bicelle stability. Furthermore, considering the inhibitory effect of reduced glutathione (GSH) on cuproptosis, a GSH-sensitive derivative of doxorubicin (cDOX) is designed to reduce intracellular GSH levels. In tumor cells, cDOX interacts with CP to preferentially induce cuproptosis and oxidative stress, facilitating chemoimmunotherapy. These interactions collectively address the challenges of cuproptosis in cancer treatment by promoting efficient copper ion accumulation, effective induction of oxidative stress, and robust immunogenic cell death, providing a promising strategy for cancer therapy.
研究领域:
肿瘤学
·
药剂学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2022
·
IF 5.738
Li Jinfei,Chen Shuangyi,Liao Yuxuan,Wang Hongyi,Zhou Dawei,Zhang Bo
Background: Metastatic disease remains the primary cause of death in patients with oral squamous cell carcinoma (OSCC), especially those who use betel nut. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are regarded as a significant component in the TME of OSCC. However, the precise mechanisms regulating CAFs in OSCC are poorly understood.Methods: Thirteen genes related to the arecoline were analyzed to explore the significant ones involved in arecoline-related OSCC metastasis. The GSE139869 (n = 10) and The Cancer Genome Atlas (TCGA)-OSCC data (n = 361) were mined for the identification of the differentially expressed genes. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the independent prognostic signatures. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the functional enrichment of selected genes, and gene set enrichment analysis of cuproptosis-related genes was completed. Spearman’s analysis and Tumor Immune Estimation Resource (TIMER) were used to visualize the correlation between the infiltration of CAFs and the gene expression. The correlation analysis of the cells and different genes, including CAF infiltration and transcripts per million expression, was assessed. The relationship between arecoline and CAFs was confirmed by cell counting kit-8 assay (CCK-8). CancerSEA was searched to identify the single-cell phenotype.Result: Arecoline-associated fibrosis-related OSCC differentially expressed genes (AFOC-DEGs), namely, PLAU, IL1A, SPP1, CCL11, TERT, and COL1A2, were screened out and selected from the Gene Expression Omnibus (GEO) database and TCGA database. AFOC-DEGs were highly expressed in OSCC, which led to poor survival of patients. Functional enrichment analysis, protein–protein interaction network construction, and Spearman’s correlation analysis all suggested that AFOC-DEGs were closely associated with cuproptosis. Cellular experiments demonstrated that arecoline stimulation could significantly increase the cell viability of CAFs. Single-sample Gene Set Enrichment Analysis (ssGSEA) results showed that GLS and MTF1 were highly expressed when fibroblasts proliferated at high enrichment levels. In addition, analysis of single-cell sequencing results suggested that OSCC cells with high expression of AFOC-DEGs were associated with OSCC metastasis.Conclusion: We found a close association between arecoline, cuproptosis, and CAFs, which might play an important role in the metastasis of OSCC.
研究领域:
肿瘤学
·
分子生物学
·
生物信息学
✓ 已验证
DOI
PubMed
高影响因子
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