EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2024
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IF 4.3
Pei Huang,Gongfa Wu,Min Huang,Yating Deng,Xuming Chen,Guodong Ye,Xiyong Yu,He Wang,Huaying Wen,Yi Zhou
The resistance of tumor cells to apoptosis often leads to chemoresistance and treatment failure in clinic. In this study, we have developed a Cu 2+ -coordinated lignosulfonate (CLS) /doxorubicin (DOX) biological complex (referred to as LCD) with the aim of overcoming cellular resistance to apoptosis for combined lung cancer therapy. The copper complexes modified by CLS exhibit significant water solubility and excellent in vivo biocompatibility. The proportion of copper in the composite is simultaneously increased. Due to the coordination and π-π stacking effects, the self-assembled LCD exhibits nanometer-scale particle size, a narrow and homogeneous grain distribution, as well as excellent dispersion stability. Furthermore, LCD has the potential to disassemble in the presence of high levels of glutathione (GSH) and low pH, leading to effective drug release. Cu 2+ -mediated cuproptosis can lead to the down-regulation of FDX1 and DLAT protein expression by reducing mitochondrial membrane potential, resulting in non-apoptotic programmed cell death (PCD) regardless of cellular resistance to apoptosis. Moreover, the released DOX not only exhibits a preference for localizing in the cell nucleus to induce apoptosis for combined chemotherapy, but also generates a substantial amount of H 2 O 2 . This H 2 O 2 further produces ROS to induce apoptosis through Fenton reaction with Cu 2+ . LCD demonstrates significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity through the combined action of cuproptosis and apoptosis. This study may provide a potential avenue for the advancement of self-delivery nanomedicine to overcome resistance to apoptosis in tumor therapy.
研究领域:
肿瘤学
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纳米医学
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药理学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Meiting Li,Zhuoyin Liu,Dan Peng,Yadong Liu,Lili Cheng,Baizhu Chen,Jie Liu
Cuproptosis has gained significant attention among different cell death pathways in cancer therapy, which relies on the excessive accumulation of Cu 2+ in mitochondria of tumor cells. Nevertheless, the high levels of glutathione in tumor microenvironment chelates with Cu 2+ and thereby reducing its cytotoxicity. In this study, we designed core-shell porous organic polymers (POPs) nanoparticles to deliver and accumulate Cu 2+ in tumor cells for enhanced cuproptosis. The porous organic polymers, containing bipyridine structural units, were synthesized on the aminated silica template, followed by the coordination of Cu 2+ and the loading of artesunate (ART) as the sonosensitizer, yielding the Cu/ART@Hpy nanoparticles. In the acidic tumor microenvironment, the nanoparticles realized pH-responsive release of Cu 2+ . Meanwhile, the generation of ROS under ultrasound irradiation depleted intracellular glutathione, leading to the increased intracellular accumulation of Cu 2+ for cuproptosis and triggering multiple cell death mechanisms for sonodynamically enhanced tumor therapy. Our study highlights the potential of the porous organic polymer as a platform for cuproptosis and synergistic tumor therapy. Statement of Significance Cuproptosis is induced by the excessive accumulation of Cu²⁺ within the mitochondria of tumor cells. However, the high level of glutathione in the tumor microenvironment can chelate Cu²⁺, thereby reducing the therapeutic efficacy. In this study, we developed the core-shell structured Cu/ART@Hpy nanoparticles for pH-responsive delivery of Cu²⁺. Under ultrasound irradiation, the generated reactive oxygen species deplete intracellular glutathione, enhancing Cu²⁺ accumulation for cuproptosis and activating multiple cell death pathways. The Cu/ART@Hpy nanoparticles enable sonodynamically enhanced cuproptosis, achieving synergistic tumor therapy.
研究领域:
生物医学工程
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癌症治疗
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材料科学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Wei Chen,Wenyu Xie,Zhimin Gao,Chen Lin,Meiling Tan,Yaru Zhang,Zhiyao Hou
A core-shell-structured Cu 2 O@Mn 3 Cu 3 O 8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)-activated copper ionophore to achieve safe and efficient cuproptosis. The Mn 3 Cu 3 O 8 shell not only prevents exposure of normal tissues to the Cu 2 O core to reduce systemic toxicity but also exhibits enhanced enzyme-mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)-like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)-like activity catalyzes the overexpressed H 2 O 2 in the TME, thereby generating O 2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton-like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress-induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme-mimicking activity. The mild photothermal effect enhances the enzyme-mimicking activity of the CMCO nanozymes, thus inducing high-efficiency ferroptosis-boosted-cuproptosis.
研究领域:
纳米技术
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癌症生物学
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治疗学
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酶模拟
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光化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Jianshuai Bao,Jiefei Wang,Sudi Chen,Shiqi Liu,Zhen Wang,Weiwei Zhang,Chenhui Zhao,Yuling Sha,Xiaoyan Yang,Yusen Li,Yong Zhong,Feng Bai
Reactive oxygen species (ROS) mediated tumor cell death is a powerful anticancer strategy. Cuproptosis is a copper-dependent and ROS-mediated prospective tumor therapy strategy. However, the complex tumor microenvironment (TME), low tumor specificity, poor therapy efficiency, and lack of imaging capability impair the therapy output of current cuproptosis drugs. Herein, we designed a dual-responsive two-dimensional metal–organic framework (2D MOF) nanotheranostic via a coordination self-assembly strategy using Au(III) tetra-(4-pyridyl) porphine (AuTPyP) as the ligand and copper ions (Cu2+) as nodes. The dual-stimulus combined with the protonation of the pyridyl group in AuTPyP and deep-penetration ultrasound (US) together triggered the controlled release in an acidic TME. The ultrathin structure (3.0 nm) of nanotheranostics promoted the release process. The released Cu2+ was reduced to Cu+ by depleting the overexpressed glutathione (GSH) in the tumor, which not only activated the Ferredoxin 1 (FDX1)-mediated cuproptosis but also catalyzed the overexpressed hydrogen peroxide (H2O2) in the tumor into reactive oxygen species via Fenton-like reaction. Simultaneously, the released AuTPyP could specifically bind with thioredoxin reductase and activate the redox imbalance of tumor cells. These together selectively induced significant mitochondrial vacuoles and prominent tumor cell death but did not damage the normal cells. The fluorescence and magnetic resonance imaging (MRI) results verified this nanotheranostic could target the HeLa tumor to greatly promote the self-enhanced effect of chemotherapy/cuproptosis and tumor inhibition efficiency. The work helped to elucidate the controlled assembly of multiresponsive nanotheranostics and the high-specificity ROS regulation for application in anticancer therapy.
研究领域:
纳米技术
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癌症治疗
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材料科学
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生物医学工程
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化学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Brain Hemorrhages
·
2025
·
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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产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhongkai Zhao,Zeyu Miao,Yuyang Hou,Yifan Zhong,Xiaorong Zhang,Xuedong Fang
Background A newly identified type of cell death due to intracellular copper accumulation is known as cuproptosis and RNA methylation is a post-transcriptional modification mechanism, both of which perform vital roles in the immune microenvironment of colorectal cancer (CRC), but the link between the two needs more research. Methods TCGA database provided RNA-seq data and details clinically of CRC samples. Cuproptosis-related RNA methylation regulators (CRRMRs) were identified by correlation analysis. We screened 6 CRRMRs for prognostic model construction by employing LASSO-Cox regression analysis and calculated risk scores by CRRMRs (CuMS). GSE39582 and GSE38832 cohort were used as external validation sets. This research concentrated on the connection between the prognostic model and somatic mutation, anti-cancer drug sensitivity, immune infiltration, immune checkpoint expression. In addition, we investigated the differential expression of YTHDC2 in epithelial cell subpopulations by single-cell analysis with GSE166555, calculated cuproptosis scores and performed pathway enrichment. In vitro experiments were performed to explore the consequences of knockdown of YTHDC2 on CRC cell proliferation and migration, as well as changes in CRC cell viability in response to elesclomol after knockdown of YTHDC2. In vivo experiments, we constructed the cell line-derived xenograft model to further validate the results of the in vitro experiments. Results The prognosis of CRC can be predicted by CuMS, which GSE39582 and GSE38832 confirmed. Two CuMS groups showed different tumor mutation burden (TMB) and immune infiltration. CuMS was connected to emerging immune checkpoints CD47 and PVR, therefore, it can be clinically complementary to TMB and microsatellite instability (MSI) status. In single-cell analysis, a subpopulation of epithelial cells with high YTHDC2 expression had a high cuproptosis score. In vitro experiments, knocking down YTHDC2 promoted cell proliferation and migration in CRC, and weaken the inhibitory effect of elesclomol and elesclomol-Cu on cell viability, which in vivo experiments validated. Conclusion We developed a prognostic model constructed by 6 CRRMRs to assess overall survival and immune microenvironment of CRC patients. YTHDC2 might regulate cuproptosis in multiple ways.
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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基因组学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ASIAN JOURNAL OF ANDROLOGY
·
2024
·
IF 3
Zhang Jing-Yi,Yu Xu-Jun,Li Jun-Jun,Xiao Yao,Li Guang-Sen,Yang Fang,Dong Liang
Cuproptosis, a novel mechanism of programmed cell death, has not been fully explored in the context of spermatogenic cells. This study investigated the potential involvement of cuproptosis in spermatogenic cell death using a mouse model of copper overload. Sixty male Institute of Cancer Research (ICR) mice were randomly divided into four groups that received daily oral gavage with sodium chloride (control) or copper sulfate (CuSO 4 ) at 50 mg kg −1 , 100 mg kg −1 , or 200 mg kg −1 , for 42 consecutive days. Mice subjected to copper overload exhibited a disruption in copper homeostasis. Additionally, significant upregulated expression of key cuproptosis factors was accompanied by a significant rise in the rates of testicular tissue cell apoptosis. Immunohistochemical analysis revealed the presence of ferredoxin 1 (Fdx1) in Sertoli cells, Leydig cells, and spermatogenic cells at various stages of testicular development, and the Fdx1-positive staining area was significantly increased in copper-overloaded mice. Mitochondrial dysfunction and decreased adenosine triphosphate levels were also observed, further implicating mitochondrial damage under cuproptosis. Further analyses revealed pathological lesions and blood−testis barrier destruction in the testicular tissue, accompanied by decreased sperm concentration and motility, in copper-overloaded mice. In summary, our results indicate that copper-overloaded mice exhibit copper homeostasis disorder in the testicular tissue and that cuproptosis participates in spermatogenic cell death. These findings provide novel insights into the pathogenic mechanisms underlying spermatogenic cell death and provide initial experimental evidence for the occurrence of cuproptosis in the testis.
研究领域:
生殖生物学
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毒理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2025
·
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
BIOMATERIALS
·
2026
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IF 12.9
Ning Cong,Lu Guo,Xiaoxuan Wang,Yading Zhao,Ting Zhao,Shuting Huang,Rui Liu,Song Ning,Xiaoying Zhou,Suyun Li,Yuye Fu,Jie Li
Cuproptosis is a novel form of cell death that relies on mitochondrial metabolism and has opened up new avenues for tumor therapy. However, resistance to cuproptosis in tumors can arise from several factors, such as their reliance on aerobic glycolysis, the high-glutathione (GSH) environment, and inefficient copper (Cu) delivery. In this study, we developed shell-core nanodroplets (NDs) approximately 280 nm in diameter, named Cu-EGCG-SHK-NDs. These NDs are composed of a liquid-gas phase-change perfluorohexane core and a carboxymethyl chitosan shell, loaded with the glycolytic inhibitor shikonin (SHK) and coated with Cu-complexed epigallocatechin gallate (Cu-EGCG), enabling targeted delivery through ultrasound (US)-targeted microbubble destruction (UTMD). The dual responsiveness of NDs to both US and pH enables precise drug release and efficient intracellular uptake. In addition, the US response enhances contrast-enhanced US imaging and triggers the generation of reactive oxygen species, subsequently depleting GSH. Both in vitr o and in vivo experiments confirm that Cu-EGCG-SHK-NDs possess excellent biocompatibility. Combined with UTMD, they can efficiently co-deliver Cu and SHK into tumour cells, inhibit glycolytic metabolism, and significantly reduce intracellular GSH levels. This synergistic mechanism enhances cuproptosis induction and achieves effective tumour growth inhibition.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Huiqi Li,Qizhuan Lin,Huanpeng Liu,Zheyan Chen,Xueliang Zhang,Liyuan Jin,Renyi Peng,Huanzhi Jin
Polystyrene nanoplastics (PS-NPs) and copper ions (Cu²⁺) are common environmental pollutants, yet their combined toxicological effects remain poorly understood. This study demonstrates that PS-NPs act as carriers of Cu²⁺, facilitating intracellular accumulation and inducing cuproptosis, a recently identified form of regulated cell death. Using zebrafish larvae and Hep G2 cells, we showed that co-exposure to PS-NPs and Cu²⁺ disrupted copper homeostasis, promoted DLAT oligomerization, impaired mitochondrial structure and function, and activated the cuproptosis pathway. Molecular docking revealed stable binding of PS-NPs and Cu²⁺ to the key regulator FDX1, further aggravating cuproptosis. FDX1 overexpression experiments confirmed its pivotal role, as enhanced expression significantly increased DLAT aggregation and cell death. This study is the first to reveal the molecular mechanism by which PS-NPs mediate FDX1-dependent cuproptosis via a “Trojan horse” effect. These findings provide novel insights into the mechanisms of nanoplastics–heavy metal co-exposure and offer a potential molecular target for mitigating environmental toxicity.
研究领域:
环境毒理学
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细胞生物学
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纳米毒理学
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生物化学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Oral Science
·
2026
·Vol. 18
·期 1
·13
·
IF 17.6
Zhou Lu,Mao Hanqing,Wen Yuanhao,Chen Zhi,Zhang Lu
Copper, predominantly present in bones, plays a crucial role in bone formation. However, when copper homeostasis is disrupted, excessive copper can trigger harmful inflammation and a novel form of cell death known as cuproptosis. The impact of cuproptosis on bone metabolism remains unclear. In this study, we demonstrated that excessive copper acts as an aggravator in osteoclastogenesis and bone resorption. We observed that the expression levels of the copper importer SLC31A1 and dihydrolipoamide S-acetyltransferase (DLAT) were positively correlated with bone loss in both human chronic apical periodontitis (CAP) tissues and mouse CAP models. Untargeted metabolomics analysis and screening of glucose metabolism enzymes revealed that glycogen synthesis was inhibited during cuproptosis. Mechanistically, excessive copper hindered glycogen synthesis via glycogen synthase 1 (GYS1), which limited the availability of glycogenolysis-derived glucose-6-phosphate (G6P) flux into pentose phosphate pathway (PPP), and was unable to yield abundant NADPH to ensure high demand of glutathione (GSH) for macrophage survival. The inhibition of glycogen synthesis intensified cuproptosis and bone-resorption activity. Moreover, excessive copper bound to H3K27me3, which further epigenetically inhibited the gene transcription of GYS1, thereby affecting glycogen synthesis and exacerbating cuproptosis and bone resorption. Furthermore, the disruption of glycogen metabolism intensified cuproptosis and promoted inflammatory bone loss in vivo. Our finding highlighted the complex interplay among copper homeostasis, glycogen metabolism, and the osteo-immune system, suggesting new therapeutic strategies for managing inflammatory bone diseases and other copper accumulation-related conditions through the metabolic reprogramming of cells.
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Tiaoyan Jiang,Tianying Jia,Yipengchen Yin,Tianyu Li,Xinran Song,Wei Feng,Sheng Wang,Li Ding,Yu Chen,Qin Zhang
Radiotherapy is crucial in local cancer management and needs advancements. Tumor cells elevate intracellular copper levels to promote growth and resist radiation; thus, targeted copper delivery to mitochondria could enhance radiotherapy by inducing cuproptosis in tumor cells. In this study, we engineered a multifunctional nanoliposome complex, termed Lipo-Ele@CuO2, which encapsulates both copper peroxide (CuO2) and the copper chelator elesclomol, which can delivery Cu ions to the mitochondria. The Lipo-Ele@CuO2 complex induces mitochondria-mediated cuproptosis in tumor cells and synergistically enhances the efficacy of radiotherapy. CuO2 acts as a copper donor and exhibits inherent sensitivity to acidic environments. Additionally, it depletes intracellular glutathione, thereby sensitizing cells to cuproptosis. Leveraging its pH-responsive properties in the acidic tumor microenvironment, the Lipo-Ele@CuO2 facilitate the controlled release of elesclomol, efficiently delivering copper ions to mitochondria at tumor sites. The combined in vitro and in vivo studies demonstrate that Lipo-Ele@CuO2-based therapy significantly improves antitumor efficacy and exhibits excellent safety profiles, effectively inducing cuproptosis in tumor cells and boosting the effectiveness of radiotherapy. Furthermore, metabolomic and transcriptomic analyses reveal that this combination therapy precipitates significant alterations in tumor energy metabolism, notably repressing genes related to iron–sulfur cluster assembly and glycolysis, thereby confirming the induction of cuproptosis. This therapeutic strategy provides a viable approach for addressing clinical radiotherapy resistance and demonstrates significant translational potential.
研究领域:
肿瘤学
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纳米医学
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辐射生物学
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代谢组学
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转化医学
✓ 已验证
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）