Journal of Advanced Research
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2025
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IF 13
Nuo-Wa Li,Xin Yao,Wei-Hong Lu,Yu-Qian Zhang,Ying-Ying Liu,Tian-Tian Zhang,Yang Zhao,Jin-Long Li
Introduction Atrazine (ATR) is a widely used herbicide in agriculture, and its residues pose a threat to biological organs, with particularly severe damage to the liver. Lycopene (LYC) is a natural pigment that exhibits beneficial effects on health, particularly liver health. However, the mechanism by which LYC mitigates liver injury induced by ATR remains unclear, and the hepatotoxicity induced by ATR requires further investigation. Objectives This study aimed to investigate cuproptosis involvement in ATR hepatotoxicity and elucidate the protective mechanisms of LYC. Methods We established both chicken animal models and cell models to investigate the effects of LYC on ATR-induced liver injury. A variety of experimental approaches were utilized to evaluate the impacts of LYC and ATR on hepatic tissue damage, mitochondrial dysfunction, oxidative stress, and markers associated with cuproptosis. Results ATR exposure was associated with increased copper ion accumulation and oxidative stress markers, along with decreased antioxidant enzyme activities. Severe liver damage and mitochondrial dysfunction were observed in ATR-treated groups through histopathological analysis, and these effects were alleviated by LYC. Mechanistic studies revealed that ATR induced the expression of cuproptosis-related proteins and metabolic markers, indicating activation of cuproptosis pathways. These effects were mitigated by LYC treatment. Strong binding affinity between LYC and ATOX1 was revealed by molecular docking. ATR-induced cuproptosis was significantly inhibited by ATOX1 knockdown, confirming its critical role. Conclusion Overall, it was determined that ATOX1-mediated cuproptosis is involved in ATR-induced liver toxicity and the therapeutic effects of LYC. The findings enrich the understanding of the pathogenesis of ATR-induced liver toxicity and provide data to support further cuproptosis studies.
研究领域:
毒理学
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分子生物学
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药理学
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环境科学
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Juan Wang,Junyu Wang,Jun Zhang,Haoran Ye,Dawei Wang,Ling Tao,Yongchao Yao,Ying Chen,Xiangchun Shen
As a notoriously incurable tumor, triple-negative breast cancer (TNBC) exhibits significant sensitivity to ferroptosis and the glutathione (GSH) antioxidant defense system plays a crucial role in its progression. Herein, we report a bimetallic chitosan/hyaluronic acid nanoparticle (5FCN, with a Fe/Cu mass ratio of 5:5) that employs a self-amplified dual mechanism of ferroptosis and cuproptosis for TNBC therapy. Hyaluronic acid in 5FCN specifically binds to the overexpressed CD44 receptor on TNBC cells. This allows 5FCN to enter cells via receptor-mediated endocytosis, then release metal ions in acidic environments. Released Fe 3+ and Cu 2+ react with GSH in tumor cells, weakening the antioxidant system and producing Fe 2+ and Cu + . These ions trigger Fenton/Fenton-like reactions with H 2 O 2 , generating toxic hydroxyl radicals (·OH) to boost ferroptosis. Meanwhile, high-valent Cu 2+ and Fe 3+ are produced, forming a cycle for GSH depletion and ·OH generation. As H 2 O 2 depletes, the rising Cu + level in cells causes lipoylated protein aggregation, amplifying cuproptosis. In vitro and in vivo studies demonstrated that 5FCN exhibited superior cell-killing efficacy against TNBC with few side effects. Collectively, 5FCN represents a potential drug to self-amplify ferroptosis/cuproptosis in TNBC.
研究领域:
肿瘤学
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纳米医学
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生物化学
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ACS Applied Materials & Interfaces
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2025
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IF 8.2
Yu-Yi Ling,Qing-Hua Shen,Liang Hao,Zhi-Yuan Li,Long-Bo Yu,Xiao-Xiao Chen,Cai-Ping Tan
Being a recently identified mode of programmed cell demise, the functional implications of cuproptosis in the genesis, progression, and therapeutic modulation of cancer remain largely unknown. Given that cuproptosis is predominantly elicited by cellular copper overload, notably attributable to the dysregulation of copper homeostasis within mitochondria, we designed a series of phosphorescent rhenium(I) complexes (Re1–Re5) as suborganelle-targeted copper ionophores. Among them, Re5 can successfully transport extracellular copper into mitochondria and the Golgi apparatus and especially enrich copper into mitochondria. Consequently, Re5 breaks the cellular redox balance and disturbs the energetic and metabolism pathways to induce cuproptosis. Finally, we prove that Re5 can promote immune responses and modulate cancer immune microenvironments. In all, we present here the first subcellular organelle-targeted copper ionophore and prove that cuproptosis-inducing small molecules are potent cancer immunotherapeutic candidates.
研究领域:
生物化学
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肿瘤学
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免疫学
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Nature Communications
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2024
·Vol. 15
·期 1
·1-17
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IF 14.7
Guan Meng,Cheng Kai,Xie Xiao-Ting,Li Yong,Ma Meng-Wen,Zhang Bin,Chen Si,Chen Wei,Liu Bo,Fan Jin-Xuan,Zhao Yuan-Di
Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu 9 S 8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy.
研究领域:
肿瘤学
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分子生物学
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纳米技术
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免疫学
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Journal for ImmunoTherapy of Cancer
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2025
·Vol. 13
·期 6
·e011472
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IF 10.6
Hong Yang,Boshao Deng,Xiao Han,Lulu Wang,Jing Zhao,Yunpei Zhao,Zihan Sun,Siyi Wang,Guokang Liu,Yuzhang Wu,Jian Chen
Background Breast cancer is the most diagnosed malignancy and a leading cause of cancer-related deaths among women globally. Cuproptosis plays a significant role in tumor progression and therapeutic response. Increasing studies suggest that targeting cuproptosis presents a promising strategy for cancer therapy, such as through the development of copper nanoparticles as therapeutic agents. However, resistance to cuproptosis has emerged as a critical hallmark of cancer. Therefore, it is essential to further investigate the mechanisms underlying cuproptosis resistance to enhance its therapy effect. Methods The relationship between breast cancer progression and the C5a/C5aR pathway or cuproptosis was determined by single-cell RNA sequencing analyses, RNA-sequence analyses, bioinformatic analyses, survival analyses and immunohistochemistry. The antitumor effects of CuS nanoparticles and C5a receptor antagonists (C5aRA) were assessed by in vitro and in vivo strategies including cell counting kit-8, colony formation assay, relative reactive oxygen species level assay, western blots, real-time quantitative PCR, immunohistochemistry, immunofluorescence assay, flow cytometry and the xenograft mice models. Complement system activation by CuS nanoparticles was tested by ELISA. Results Our results indicated that activation of the C5a/C5aR pathway contributes to cuproptosis resistance by upregulating ATP7B expression via the Wnt/β-catenin pathway. Consequently, combining CuS nanoparticles with lazer treatment and C5aRA markedly enhanced the antitumor efficacy of CuS nanoparticles by overcoming cuproptosis resistance, leading to a synergistic effect in cancer therapy that included cuproptosis-targeting therapy, immunotherapy, and photothermal therapy. Conclusions This study reports, for the first time, proved C5a/C5aR pathway-mediated cuproptosis resistance in cancer cells, and combining CuS nanoparticles and C5aRA offers a superior and novel therapeutic strategy for cancer.
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ENVIRONMENTAL POLLUTION
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2026
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IF 7.2
Luyao Zhang,Danyang Zhang,Silu Li,Bufan Xu,Fan Jiang,Yufan Nie,Guoliang Li
Copper oxide nanoparticles (CuO NPs), with their superior catalytic activity, antimicrobial performance and photoelectric properties, are widely used in production and daily life, thereby increasing their environmental release risk. Compared with the well-studied effects of ionic copper, the chronic toxicity of CuO NPs remains largely overlooked. In this study, zebrafish were exposed to environmentally relevant concentrations (5 mg/L Cu) of CuO NPs or copper sulfate (CuSO 4 ) to systematically evaluate intestinal toxicity induced by long-term exposure to different forms of copper. An integrated strategy incorporating ultrastructural analysis, biochemical assays, gut microbiota profiling, and metabolomic analysis was employed. Both copper forms induced mitochondrial damage, metabolic perturbations, and gut microbial dysbiosis in intestinal epithelial cells. However, CuO NPs showed markedly stronger intestinal toxicity than ionic copper. Specifically, CuO NPs can directly penetrate mitochondria in particulate form, impair mitochondrial structure, and potently activate the FDX1-LIAS-DLAT cuproptosis pathway, thereby triggering significant disturbances in amino acid, lipid, and nucleotide metabolism. Furthermore, CuO NPs exerted a more robust impact on the bidirectional gut microbiota-host metabolite interactions. In conclusion, this study clarifies form-dependent differences in copper-induced intestinal toxicity and highlights the critical role of microbiota-metabolite crosstalk in CuO NP-mediated adverse effects. These findings yield critical mechanistic insights and provide a robust scientific basis for evaluating the potential health risks posed by chronic exposure to CuO NPs.
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CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Tianle Zhou,Haoyang Du,Su Zhao,Gen Li,Siyu Wang,Sikai Wang,Jinfeng Ning,Manjie Zhang,Hang Yin
Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide, with therapeutic progress hindered by the immunosuppressive and heterogeneous tumor microenvironment (TME). Protein arginine methyltransferase 3 (PRMT3), a key regulator of post-translational modifications (PTMs), plays a pivotal role in immune evasion and therapeutic resistance by modulating key oncogenic and immune pathways. Despite the potential of PRMT3 inhibitors, such as SGC707, their clinical efficacy is limited by poor pharmacokinetics, inadequate therapeutic durability, and the complex interplay within the TME. To address these challenges, we developed a multifunctional nanoplatform, poly (acrylic acid)‑copper bismuth tellurium@SGC707 nanospheres (PAA-CuBiTe@SGC707 NSs), which integrates copper-induced cell death (cuproptosis), radiosensitization, and PRMT3 inhibition to achieve synergistic therapeutic outcomes. The nanoplatform induces mitochondrial DNA (mtDNA) release, thereby activating a cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-mediated immunogenic response, which is further amplified by SGC707 through the suppression of PRMT3-mediated arginine methylation of cGAS. Furthermore, the incorporation of Bi and Te nanoparticles endows the nanoplatform with effective radiosensitization capability, improving the precision and efficacy of radiotherapy. This study presents a novel nanotechnology-driven therapeutic strategy that simultaneously addresses immune resistance and radiotherapy limitations, providing a promising approach for improving NSCLC treatment outcomes.
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Advanced Healthcare Materials
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2023
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IF 10
Yihang Ruan,Huilan Zhuang,Xuemei Zeng,Lili Lin,Xuechun Wang,Panpan Xue,Shan Xu,Qi Chen,Shuangqian Yan,Wei Huang
The colon tumor microenvironment has a high concentration of H 2 S and glutathione, which is highly immunosuppressive and adverse to multiple therapeutic methodologies such as ferroptosis. Here, an engineered microbial nanohybrid based on Escherichia coli ( E. coli ) and Cu 2 O nanoparticles to specific colon tumor therapy and immunosuppression reversion is reported. The as-prepared E. coli @Cu 2 O hybrid can accumulate in tumor sites upon intravenous injection, and Cu 2 O nanoparticles convert to Cu x S by consuming the endogenous H 2 S, which exhibits strong photothermal conversion at near-infrared II (NIR II) biological window. Furthermore, E. coli @Cu 2 O is able to induce cellular ferroptosis and cuproptosis through inactivation of glutathione peroxidase 4 and aggregation of dihydrolipoamide S-acetyltransferase, respectively. Photothermal-enhanced ferroptosis/cuproptosis achieved by E. coli @Cu 2 O reverses the immunosuppression of colon tumors by triggering dendritic cell maturation (about 30%) and T cell activation (about 50% CD8 + T cells). Concerted with immune checkpoint blockade, the engineered microbial nanohybrid can inhibit the growth of abscopal tumors upon NIR illumination. Overall, the designed microbial nanohybrid can achieve tumor-specific photothermal-enhanced ferroptosis/cuproptosis and immunosuppression reversion, showing promise in precise tumor therapy in future clinical translation.
研究领域:
癌症治疗
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纳米技术
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免疫学
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生物医学工程
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材料科学
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JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Tiantian Liu,Zehang Zhou,Mengxing Zhang,Puxin Lang,Jing Li,Zhenmi Liu,Zhirong Zhang,Lin Li,Ling Zhang
The cuproptosis cell death pathway brings fresh opportunities for tumor therapy. However, efficient and targeted cuproptosis induction in tumors is still a challenge. Unfortunately, the well-known cuproptosis initiator, disulfiram and copper complex (DSF/Cu 2+ ), also increases PD-L1 level in tumors, which may diminish the final therapeutic outcome. In this study, DSF/Cu 2+ -loading MXene nanosheets are coated with PD-1 overexpressing T cell membrane to generate CuX-P system. CuX-P could recognize and stick to PD-L1 on tumor cells like a patch, which promotes the endocytosis of both CuX-P and PD-L1 by tumor cells. Following internalization and release of DSF/Cu 2+ in the cytoplasm, PD-L1 expression is upregulated. However, due to the presence of CuX-P in the tumor microenvironment , the then supplemented PD-L1 on tumor surface again binds CuX-P for internalization. This feedback loop keeps blocking and consuming the PD-L1 on tumor surface and promotes the enrichment of CuX-P in tumors to induce cuproptosis. After CuX-P treatment with laser irradiation, strong anti-tumor immune responses are stimulated in a mouse model with triple-negative breast cancer. Thus, this study develops a tumor-targeted biomimetic system that offers simultaneous cuproptosis killing, photothermal therapy (PTT) and immunotherapy in mice.
研究领域:
肿瘤学
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免疫治疗
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纳米技术
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癌症生物学
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Lihua Wang,Yang Deng,Xionghongcan Zhou,Kaiyue Song,Cong Jiang,Feng Zhao,Xianglong Li
Cuproptosis holds promise for breast cancer therapy, yet systemic copper delivery risks off-target toxicity, and intrinsic tumor resistance mechanisms limit its therapeutic efficacy. To overcome this obstacle, a biodegradable hybrid nanomedicine (designated CaO 2 @CuPDA) was designed to dual-amplify cuproptosis through Ca 2+ -overload and photothermal effects for potent immunotherapy. The nanomedicine comprises a calcium peroxide (CaO 2 ) core encapsulated within a copper–polydopamine shell, which stabilizes CaO 2 against premature hydrolysis and confers tumor microenvironment-responsive behavior, photothermal capability, and controlled Cu 2+ release. Upon exposure to the acidic, glutathione (GSH)-rich tumor microenvironment, CaO 2 @CuPDA disintegrates, concurrently releaseing Cu 2+ /Ca 2+ and generating H 2 O 2 . The Fenton-like reaction catalyzed by GSH-reduced Cu + converts H 2 O 2 into hydroxyl radicals, elevating intracellular oxidative stress. Simultaneously, FDX1-mediated reduction of excess Cu 2+ to Cu + inhibits the synthesis of iron‑sulfur cluster proteins to trigger cuproptosis. Critically , this cuproptosis degree is dramatically potentiated by Ca 2+ -overload, increased ROS, and photothermal effects. The amplified cuproptosis elicits robust releasing damage-associated molecular patterns (DAMPs) that activate dendritic cells and recruit cytotoxic T lymphocytes, leading to potent antitumor immunity and suppressed tumor growth in vivo. This work presents a safe and efficient nanoplatform for cuproptosis potentiation, providing a novel strategy for breast cancer treatment.
研究领域:
纳米医学
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癌症治疗
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生物无机化学
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光热治疗
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免疫治疗
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活性氧信号传导
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药物递送系统
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International Journal of Nanomedicine
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2025
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IF 6.5
Yutong Chen,Jin Wang,Daniel Zheng,Weiyu Zhang
Objective Radioimmunotherapy (RIT) is a promising treatment for deep-seated and metastatic tumors, but its efficacy is limited by the immunosuppressive tumor microenvironment (TME) and a narrow therapeutic window. This study aimed to develop a novel nanoplatform to overcome these constraints by simultaneously sensitizing tumors to radiation, inducing cuproptosis, and reprogramming the immunosuppressive TME.Methods We engineered a PEGylated copper-loaded black phosphorus nanoplatform (BPNS@Cu-PEG). Its functionality as a radiosensitizer and cuproptosis inducer was evaluated. The mechanisms of TME reprogramming were investigated, including glutathione (GSH) depletion, reactive oxygen species (ROS) amplification, hypoxia alleviation, and M2-to-M1 macrophage repolarization. Furthermore, we systematically evaluated its antitumor immune effects in vitro and in vivo.Results BPNS@Cu-PEG was synthesized with a high copper incorporation rate of 93%. In vitro cellular assays confirmed that the internalized nanoplatform effectively induced cuproptosis and immunogenic cell death (ICD) while simultaneously regulating the TME. In vivo, BPNS@Cu-PEG not only potently inhibited tumor progression and stimulated robust antitumor immunity under low-dose radiotherapy but also exhibited an excellent safety profile.Conclusion This work establishes a copper-based, low-dose radioimmunotherapy strategy. The BPNS@Cu-PEG nanoplatform presents a viable and potent strategy to counteract radioresistance and promote systemic antitumor immunity, potentially broadening the therapeutic application and safety profile of RIT.
研究领域:
纳米医学
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癌症免疫治疗
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放射肿瘤学
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肿瘤生物学
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材料科学
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Luyao Xu,Jing Feng,Shihao Xu,Mingli Jin,Xianyue Bai,Hui Zhang,Minghui Zhu,Shengmin Lin,Jiaxing Song,Cuixia Lu
Multimodal targeted combination therapy that harnesses synergistic effects has emerged as a transformative paradigm in cancer therapy, progressively replacing traditional monotherapy. Herein, we report a tumor microenvironment (TME)-responsive multifunctional nanoplatform Cu-Ce6@DHA NPs (CCD NPs), which is self-assembled through the coordination of Cu²⁺, the antitumor drug dihydroartemisinin (DHA), and the photosensitizer chlorin e6 (Ce6). This nanoplatform enables the near-infrared-triggered combination of cuproptosis and ferroptosis for tumor treatment. Upon internalization by tumor cells, these nanoparticles undergo glutathione (GSH)-triggered disintegration, releasing their encapsulated payloads within the TME. The released Ce6 mediates potent photodynamic therapy (PDT) under laser irradiation, and DHA undergoes GSH-dependent activation to generate cytotoxic reactive oxygen species (ROS) and suppresses glutathione peroxidase 4 (GPX4), thereby amplifying ferroptotic cell death. Concurrently, the released copper ions deplete intracellular GSH and further inhibit GPX4, which exacerbates lipid peroxidation and promotes ferroptosis. Notably, the intracellular accumulation of copper ions disrupts mitochondrial metabolism by destabilizing iron-sulfur cluster (Fe-S) proteins and inducing oligomerization of lipoylated lipoylated dihydrolipoamide S-acetyltransferase (DLAT), ultimately triggering cuproptosis. Therefore, our findings establish a novel nanoplatform that simultaneously exploits metabolic vulnerabilities (via cuproptosis), redox imbalances (via ferroptosis), and photodynamic effects, providing a promising multimodal therapeutic strategy for cancer treatment.
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高影响因子
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