Biomaterials Advances
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2025
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IF 6
Yixun Zhang,Wenjie Xie,Jinchuang Li,Zhenguo Liang,Xin Zhou,Zeheng Tan,Zhenjie Wu,Jundong Lin,Yangjia Zhuo,Fen Zou,Biyan Wen,Jianwei Chen,Shanghua Cai,Jianheng Ye,Yingke Liang,Jianming Lu,Huikang Yang,Weide Zhong,Ronghua Yang
Melanoma, a highly aggressive skin cancer, continues to challenge current therapeutic modalities due to its resistance and high mortality rates. Recent advancements highlight cuproptosis, a copper-driven form of programmed cell death, as a promising target for melanoma treatment. This study integrated machine learning and large-scale genomic data to identify FDX1 as a pivotal gene in cuproptosis-related pathways for melanoma. We developed a novel nanomedicine, ACM@MCHS-CuMOF@Dox, combining Mesoporous Carbon Hollow Spheres (MCHS) loaded with Copper-based Metal-Organic Frameworks (CuMOFs) and Doxorubicin (Dox), to exploit this discovery. The nanomedicine leverages a biomimetic approach by incorporating A375 cell membranes, enhancing tumor-targeted delivery. Physicochemical characterization confirms optimal drug loading and pH/GSH-responsive release profiles. In vitro studies demonstrate that ACM@MCHS-CuMOF@Dox inhibits melanoma cell proliferation, migration, and invasion, outperforming other formulations. Mechanistic investigations revealed that ACM@MCHS-CuMOF@Dox induced robust apoptosis and cuproptosis through FDX1 downregulation, thereby enhancing oxidative stress and therapeutic efficacy. These findings underscore the potential of combining machine learning-driven target identification with advanced nanomedicine for precision melanoma therapy. This approach offers a promising strategy for overcoming current treatment limitations and advancing personalized cancer care.
研究领域:
肿瘤学
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纳米医学
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生物信息学
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DOI
PubMed
高影响因子
Brain Hemorrhages
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2025
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IF 1.4
Wenying Zhang,Wanyu Ma,Siying Ren,Likun Wang,Guofeng Wu
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability. Cuproptosis is a regulatory cell death modality dependent on intracellular copper ion concentration, the role of which in ICH is unclear. Upon activation by ligand agonists, peroxisome proliferator-activated receptor-γ (PPARγ), can alleviate brain injury after ICH. To investigate the inhibitory effect of activating PPARγ on cuproptosis following ICH, we established the ICH model in vivo and in vitro and they were treated with the PPARγ agonist or antagonist after models being established successfully. Then, the copper ion concentration was measured by copper colorimetric assay and the expression of cuproptosis-related regulatory factors and copper transporter 1 was detected by western blotting and immunofluorescence staining (except in the cell level). We found that the increase in copper ion concentration following ICH leads to the disruption of copper homeostasis, inducing cuproptosis via copper toxicity. Activating PPARγ regulates the expression of cuproptosis-associated positive or negative regulatory factors and mitigates copper toxicity by inhibiting the influx of copper ions into the cell, thereby inhibiting cuproptosis. This study not only reveals the relationship between ICH and cuproptosis but also may provide new therapeutic strategies for improving the prognosis of patients with ICH.
研究领域:
神经科学
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分子生物学
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DOI
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 11
·e70636
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IF 4.2
Hao Zhang,Guoyan Liu
Gastric cancer is a common malignant tumour. Copper‐induced cell death, a recently discovered form of metal ion‐related cell death, has garnered significant attention from researchers. We synthesised a multifunctional nanoparticle, ZnO@CuEA, and characterised its morphology using transmission electron microscopy. Cytotoxicity was analysed via CCK8 assays and calcein‐AM staining. The tumour‐targeting capability of ZnO@CuEA was validated using confocal microscopy and in vivo imaging experiments. RNA‐seq and proteomic analysis were conducted to assess changes in mRNA and protein expression before and after ZnO@CuEA treatment. Lysosomal β‐galactosidase staining was employed for cellular senescence detection, and protein expression levels were analysed via Western blot. Finally, in vivo experiments demonstrated the tumour‐inhibitory effect of ZnO@CuEA. ZnO@CuEA is a multifunctional nanoparticle capable of targeting tumour cells and inducing cuproptosis. In vivo experiments showed that ZnO@CuEA exhibits significant antitumor activity. The multifunctional nanoparticles synthesised in this study provide a novel therapeutic approach for cancer treatment.
研究领域:
肿瘤学
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分子生物学
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材料科学
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DOI
PubMed
高影响因子
Redox Biology
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2025
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IF 11.9
Zhanliang Jiang,Jin Li,Mingpeng Shi,Yunfei Li,Ning Sun,Kai Xi,Xiangyan Li,Daqing Zhao,Xiangyang Leng,Zhenwei Zhou,Haisi Dong
Aberrant changes in the hypoxic microenvironment are implicated in osteoarthritis (OA) development. Cuproptosis, a unique copper-dependent form of regulated cell death that depends on the activity of key enzymes in mitochondrial metabolism, is also linked to oxygen levels. However, the crosstalk among hypoxic environment, cuproptosis, and OA development remains unclear. This study confirmed that oxygen levels in the OA model gradually increased during OA progression, which suppressed the expression of anabolic genes for articular cartilage extracellular matrix, upregulated catabolic genes, and increased the cell death rate of primary chondrocytes. Mechanistically, oxygen elevation upregulated the expression of solute carrier family 31 member 1 (SCL31A1), a transmembrane pump facilitating copper uptake, whereas it downregulated the expression of ATPase copper transporting beta (ATP7B), a copper chaperone facilitating copper efflux, leading to aberrant copper accumulation in the cells. Ultimately, this accumulation efficiently induces oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), triggering cell death, known as cuproptosis. Hypoxia-inducible factor-1α (HIF-1α), induced under hypoxic conditions, is negatively correlated with DLAT and the severity of OA, as confirmed in human and rat cartilage. Furthermore, siRNA-mediated HIF-1α silencing sensitized primary chondrocytes to cuproptosis, whereas HIF-1α stabilization had protective effects. In summary, increased oxygen levels in the cartilage induce cuproptosis, thereby accelerating OA progression, whereas HIF-1α stabilization mitigates this process. These findings may provide novel therapeutic targets for OA treatment in clinical practice.
研究领域:
分子生物学
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病理学
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细胞生物学
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生物医学
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DOI
PubMed
高影响因子
Journal of Inflammation Research
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2025
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IF 4.1
Qiaohui Ren,Xinyue Zhu,Nannan Wang,Kang Yu,Wei Lv,Lianzi Wang,Yan Zang,Dongyue Ma,Xinyi Zhou,Junxiao Yao,Mengjiao Shen,Li Yu,Tao Li
Purpose We explored the effects of miR-133a-5p and ATP7B on cuproptosis in hepatocellular carcinoma.Methods Initially, we assessed the impact of miR-133a-5p on hepatocellular carcinoma (HCC) using CCK-8 assays, cell scratch assays, and flow cytometry. Subsequently, we utilized elesclomol in combination with copper ions to induce cuproptosis in the HCC cell lines PLC/PRF/5 and Huh-7. We evaluated the influence of miR-133a-5p on cuproptosis using CCK-8 assays, cell scratch assays, flow cytometry, and Western blotting. To elucidate the underlying mechanisms, we employed bioinformatics to identify potential downstream target genes of miR-133a-5p and conducted dual-luciferase reporter assays to confirm the binding sites. Finally, we validated the regulatory effect of miR-133a-5p on ATP7B by modulating miR-133a-5p expression through cell transfection experiments.Results The results from the CCK-8 assay, cell scratch assay, and flow cytometry demonstrated that miR-133a-5p significantly inhibits the proliferation and migration of HCC cells while promoting their apoptosis. Furthermore, Elesclomol in combination with copper ions induces cuproptosis in HCC cells. Compared to the cuproptosis observed in HCC as a control, miR-133a-5p further suppresses the proliferation and migration of HCC cells, enhances their death, and increases the expression of cuproptosis-related proteins more prominently. Bioinformatics analysis suggested that ATP7B might be a downstream target gene of miR-133a-5p. This was confirmed by dual luciferase assays, which identified a binding site between miR-133a-5p and ATP7B. Additionally, the expression levels of ATP7B were found to decrease or increase in response to the regulation by miR-133a-5p.Conclusion MiR-133a-5p facilitates cuproptosis in hepatocellular carcinoma through targeting of ATP7B.
研究领域:
肿瘤学
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分子生物学
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遗传学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2025
·Vol. 44
·期 1
·1-25
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IF 12.8
Wang Pengyu,Guo Weihua,Liu Shuyue,Li Shouyi,Li Jiaqi,Ding Bowen,Yin Fengyi,Yang Yang,Li Xingjiang,Cao Pei,Ma Chaozhe,Zhang Wanying,Song Yidan,Geng Yating,Liu Lantao,Hu Jing,Hao Jihui,Feng Yukuan
Background Copper accumulation triggers mitochondrial-driven cell death, known as cuproptosis, offering a promising mechanism for targeted cancer therapy. Recent studies have highlighted the critical role of intratumoral copper levels in regulating the expression of programmed cell death ligand-1 (PD-L1), suggesting that copper-induced cuproptosis not only enhances cancer cell death but may also amplify the effects of anti-PD-L1 antibodies (αPD-L1). However, in tumors where monotherapy with αPD-L1 shows limited efficacy, particularly in pancreatic ductal adenocarcinoma (PDAC), the role of copper-induced cuproptosis in enhancing αPD-L1 treatment efficacy and its underlying mechanisms remain unclear. Meanwhile, inadequate tumor drug accumulation and glycolysis significantly restrict the efficacy of cuproptosis. To address these challenges, we have synthesized a novel nanozyme, Pt@PCN-Cu, designed to stabilize intracellular copper accumulation and effectively induce cuproptosis. Additionally, we aim to determine whether this strong induction of cuproptosis can synergize with αPD-L1 to enhance cancer therapy, ultimately paving the way for novel strategies to improve PDAC treatment. Methods Pt@PCN-Cu was synthesized via a one-pot method, and its therapeutic potential was assessed in combination with αPD-L1 for the treatment of PDAC. Initially, the material’s properties were characterized, and its efficient cellular uptake was confirmed. Anti-tumor efficacy was evaluated by inducing cuproptosis in PDAC cell lines and xenograft models. RNA sequencing (RNA-seq) was utilized to identify key regulators involved in the modulation of PD-L1 expression by cuproptosis. Lastly, the therapeutic efficacy of Pt@PCN-Cu combined with αPD-L1 was evaluated in vivo, focusing on tumor growth inhibition and immune modulation within the tumor microenvironment (TME). Results Pt@PCN-Cu demonstrates excellent physicochemical properties and remarkable cascade catalytic activity, providing a solid foundation for further in vitro and in vivo studies. In vitro, Pt@PCN-Cu efficiently transports copper and induces cuproptosis primarily through mitochondrial dysfunction. Mechanistic studies show that Pt@PCN-Cu triggers the dissociation of hexokinase 2 (HK2) from mitochondria, leading to a reduction in HK2 activity. This decline in HK2 activity impairs glycolysis, a metabolic pathway essential for tumor energy metabolism, which in turn results in elevated PD-L1 levels. In vivo, Pt@PCN-Cu demonstrates excellent safety and accumulates at the tumor site in a subcutaneous PDAC mouse model, inducing cuproptosis. Moreover, the combination of Pt@PCN-Cu with αPD-L1 further enhanced its therapeutic efficacy and effectively reprogrammed the immunosuppressive TME. Conclusion This study presents strong evidence confirming the safety and therapeutic potential of Pt@PCN-Cu in PDAC treatment. Importantly, Pt@PCN-Cu not only induces cuproptosis but also significantly enhances antitumor efficacy in combination with αPD-L1 by regulating PD-L1 expression through HK2 modulation. These findings underscore a more effective and innovative approach for treating PDAC.
研究领域:
肿瘤学
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分子生物学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Nanoscale Horizons
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2025
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IF 6.6
Xiao Wan Han,Xu Chen,Tianle Yang,Ying Yi Luo,Rui Xue Liang,San Qi An,Xinli Liu
Cuproptosis has recently received much attention in cancer treatment. However, copper ionophores don’t show the obvious clinical efficacy. Although some Cu-based and copper ionophores-loaded nanomaterials have been applied to induce cuproptosis, it is difficult to achieve the clinical translation limited by the complicated composition, harsh synthesis condition, external stimulus, and potential biotoxicity. Phytic acid, a naturally occurring organic phosphorus carbohydrate, possesses distinct antineoplastic effect on multiply types of cancer and high biocompatibility. Based on metal-phosphonate coordination, a novel Cu-phytic acid nanozyme (denoted as CP) with pH/GSH dual-response was fabricated by a “one-spot” method. CP with three enzyme-mimicking activities enhanced cuproptosis therapy through GSH depletion, reactive oxygen species augment, hypoxia relief and the attenuation of glycolysis. As a proof of concept, Elesclomol (a copper ionophore)-resistant A549 cells were used to investigate CP- induced cuproptosis for inhibition of tumor growth in vitro and in vivo.
研究领域:
生物医学
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纳米技术
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肿瘤学
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DOI
PubMed
高影响因子
Matter
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2025
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IF 17.5
Wenting Chen,Songjing Zhong,Qian Cai,Zhuoheng Jiang,Quanhong Hu,Chuyu Tang,Qinyu Zhao,Zhuo Wang,Shaobo Wang,Xinyu Zheng,Fei Liang,Hai-Dong Yu,Linlin Li
Cutaneous melanoma, a prevalent and highly aggressive malignancy with poor prognosis, frequently leads to postoperative recurrence, presenting a significant therapeutic challenge. One of the promising cancer therapeutic methods is the induction of cuproptosis, a copper-triggered modality of mitochondrial cell death. However, its therapeutic efficacy is often limited by insufficient copper uptake and intracellular accumulation. Herein, we present a flexible and self-powered electronic patch by integrating an ultra-thin triboelectric nanogenerator (TENG) with copper-loaded nitrogen-doped carbon nanoparticles (Cu(II)-NC NPs). Extensive experimental and molecular dynamics simulation results demonstrate that the triboelectric field efficiently modulates plasma membrane permeability and fluidity, facilitating the uptake of Cu(II)-NC NPs into melanoma cells. The resulting intracellular copper accumulation increases the production of hydroxyl radicals and the depletion of glutathione, synergizing with cuproptosis to amplify copper-induced cell death. In a mouse model with incomplete melanoma resection, the patch effectively inhibits melanoma recurrence, offering a novel therapeutic paradigm to promote cancer therapy.
研究领域:
肿瘤学
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生物医学工程
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材料科学
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产品关联
DOI
高影响因子
Heliyon
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2024
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IF 3.4
Rujun Chen,Yating Huang,Ke Sun,Fuyun Dong,Xiaoqin Wang,Junhua Guan,Lina Yang,He Fei
Ovarian cancer (OCa) is a common malignancy in women, and the role of cuproptosis and its related genes in OCa is unclear. Using the GSE14407 dataset, we analyzed the expression and correlation of cuproptosis-related genes (CRGs) between tumor and normal groups. From the TCGA-OV dataset, we identified 20 cuproptosis-related long non-coding RNAs (CuLncs) associated with patient survival through univariate Cox analysis. OCa patients were divided into early-stage and late-stage groups to analyze CuLncs expression. Cluster analysis classified patients into two clusters, with Cluster1 having a poorer prognosis. Significant differences in “Lymphatic Invasion” and “Cancer status” were observed between clusters. Seven CRGs showed significant expression differences, validated using the human protein atlas (HPA) databases. Immune analysis revealed a higher ImmuneScore in Cluster1. GSEA identified associated signaling pathways. LASSO regression included 11 CuLncs to construct and validate a survival prediction model, classifying patients into high-risk and low-risk groups. Correlations between riskScore, Cluster phenotype, ImmuneScore, and immune cell infiltration were explored. Cell experiments showed that knocking down AC023644.1 decreases OCa cell viability. In conclusion, we constructed an accurate prognostic model for OCa based on 11 CuLncs, providing a basis for prognosis assessment and potential immunotherapy targets.
研究领域:
肿瘤学
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生物信息学
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分子生物学
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DOI
PubMed
高影响因子
Science Advances
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2025
·Vol. 11
·期 7
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IF 12.5
Meixiang Zhang,Xinran Song,Yu Qin,Yuanyuan Peng,Shanshan Zhang,Wei Feng,Hui Huang,Yu Chen,Jianqiao Zhou
Cuproptosis, a distinct cell death pathway, has been integrated into nanomedicine for disease theranostics. However, current nanosystems inducing cuproptosis rely on exogenous toxic copper ions, limiting the scope of biomaterials. Developing nanoplatforms that induce cuproptosis without exogenous copper holds substantial promise. Here, we engineered a two-dimensional iron (Fe) single-atom–doped molybdenum disulfide (MoS2) piezocatalyst (Fe-MoS2) for tumor therapy. Incorporating single Fe atoms enhances MoS2 piezoelectric polarization via charge redistribution and modulates Fe and Mo oxidation states, enabling multifaceted enzymatic activities, including peroxidase-, glutathione oxidase–, oxidase-, and catalase-like activities. Upon ultrasound stimulation, the Fe-MoS2 nanocatalyst generates reactive oxygen species and depletes glutathione via synergistic piezocatalytic and enzyocatalytic effects, disrupting copper ion homeostasis and inducing cuproptosis, concurrently triggering ferroptosis and ferritinophagy, which collectively enhances tumor suppression. This study represents the first paradigm to introduce a copper-free piezocatalyst for initiating cuproptosis, substantially advancing the applications of cuproptosis in tumor therapy.
研究领域:
纳米医学
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生物材料科学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Tao Bai,Luhao Wang,Zhentao Qiao,Zhiwei Wang
Diabetic patients are considered as the high risk population to develop critical limb ischemia (CLI), a peripheral vascular disease (PVD) resulted from atherosclerosis. Cuproptosis is a novel copper-dependent cell death that has shown the regulatory role in diabetes, while its effect on diabetic CLI has not been explored yet. In this study, Diabetic CLI mice was induced by femoral artery ligation (FAL) on diabetic mice. Endothelial injury in diabetic CLI was mimicked in human microvascular endothelial cells (HMEC-1) via the induction with high glucose (HG) and nutrient deprivation (ND). Besides, copper chelator Ammonium Tetrathiomolybdate (TM), which has shown the anti-cuproptosis property, was administrated to explore its potential effects on diabetic CLI mice and HG/ND-induced HMEC-1 cells. Strikingly, obvious cuproptosis was found in the gastrocnemius muscles of diabetic CLI mice and HG/ND-induced HMEC-1 cells, as evidenced by the copper overload and dysregulated cuproptosis-related proteins (such as Fe-S cluster proteins, copper exporter ATP7A, and copper importer SLC31A1). More importantly, TM protected against the hindlimb ischemic damages in diabetic CLI mice and alleviated cuproptosis-associated cell deaths in HG/ND-induced HMEC-1 cells. In summary, this study indicates the involvements of cuproptosis in diabetic CLI, and provides novel insights into copper chelator TM on diabetic CLI therapy.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Hui Zhi,Weimin Yin,Shiyu Chen,Xiaoyou Zhang,Zichen Yang,Fulong Man,Rongjie Li,Yanni Cai,Yang Li,Caoyi You,Yan Li,Yongyong Li,Haiqing Dong
Cuproptosis and ferroptosis exhibit superior synergistic advantages in antitumor therapy. While glutathione (GSH) has been identified as a key molecule in enhancing the synergistic effects of these two processes, inherent cellular redox homeostasis mechanisms limit its therapeutic efficacy. This inspired us to explore other new regulators to potentiate the synergistic effect. Through bioinformatics analysis and preliminary experimental validation, we discovered that lactate metabolism is closely associated with both ferroptosis and cuproptosis. Therefore, this work strategically targets lactate metabolism to synergistically activate cuproptosis and ferroptosis, and elucidate its immunotherapeutic mechanisms. For this purpose, we constructed a Syr-loaded nanodelivery system (Syr@mPDA@CP) using biocompatible mesoporous polydopamine (mPDA) as the carrier. Upon targeted to tumor tissues, the released Syr significantly inhibits lactate efflux, leading to intracellular lactate accumulation. This lactate buildup further induces intracellular acidification, exerting dual effects: (1) promoting ferritin (FTH1) dissociation to release endogenous iron stores, thereby elevating intracellular iron levels; and (2) suppressing glycolysis and reducing ATP levels, which inactivates the copper export protein ATP7B. Combined with copper peroxide (CP)-derived Cu 2+ , these effects synergistically amplify intracellular copper accumulation. The elevated intracellular Cu and Fe concentrations subsequently induce dual cell death pathways of cuproptosis and ferroptosis, effectively enhancing cancer immunotherapy. This study pioneers a lactate metabolism-regulating strategy to synergistically amplify both ferroptosis and cuproptosis, offering novel perspectives for antitumor therapy.
研究领域:
生物医学工程
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肿瘤学
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免疫学
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生物化学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）