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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EXPERIMENTAL NEUROLOGY
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2026
·
IF 4.8
Shiyao Feng,Boyu Sun,Longlong Tian,Mingkang Li,Guozhu Sun
Traumatic brain injury (TBI) is one of the most prevalent neurological disorders and a major cause of death and disability worldwide. Cuproptosis is a recently identified form of cell death. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that has been widely investigated in TBI, may contribute to the regulation of cuproptosis. In this study, we investigated the role of cuproptosis in TBI and the regulatory mechanisms of Nrf2. We found that cuproptosis was induced following TBI in both patients and mouse models. In TBI mice, cuproptosis peaked at 3 days post-injury and predominantly occurred in neurons. Nrf2 deficiency aggravates neuronal cuproptosis after TBI, primarily through IRF7-mediated upregulation of SLC31A1. The Nrf2 activator dimethyl fumarate (DMF) suppresses neuronal injury and improves neurological function in TBI mice by inhibiting cuproptosis. Our results establish that cuproptosis is an important mechanism in TBI and that activation of Nrf2 mitigates TBI-induced cuproptosis by regulating the IRF7–SLC31A1 axis.
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ENVIRONMENT INTERNATIONAL
·
2026
·
IF 10.2
Fengyi Zhang,Rongke Hu,Wenqi Sun,Bendong Shi,Yujie Yao
Nano-Se alleviates DON-induced cuproptosis in chicken kidney. • Nano-Se mitigates DON-induced mitochondrial oxidative damage by suppressing cuproptosis. • Nano-Se prevents DON-induced lysosomal membrane permeabilization and mitophagic flux blockage by inhibiting mitochondrial oxidative damage. • Nano-Se attenuates DON-evoked renal inflammation by restoring mitophagic flux. Deoxynivalenol (DON) is a widespread mycotoxin contaminating cereal grains and animal feed, posing significant risks to livestock health and food safety. However, the molecular mechanisms underlying DON-induced nephrotoxicity remain poorly understood. In this study, we identify cuproptosis as a critical driver of DON-induced nephrotoxicity in chickens and investigate the protective role of nano-selenium (Nano-Se). DON exposure disrupted copper homeostasis and induced cuproptosis, as evidenced by dysregulation of FDX1, LIAS, and DLAT, resulting in mitochondrial oxidative damage and electron transport chain (ETC) dysfunction. Excessive mitochondrial reactive oxygen species (mtROS) further impaired lysosomal acidification, resulting in lysosomal membrane permeabilization (LMP) and blockade of mitophagic flux, ultimately triggering a robust inflammatory response. Nano-Se supplementation effectively mitigated DON-induced renal injury by suppressing cuproptosis, restoring mitochondrial redox balance, preserving ETC function, rescuing lysosomal function, re-establishing mitophagic flux, and attenuating inflammatory responses in vivo and in vitro. Mechanistically, pharmacological modulation targeting copper levels, mtROS generation, or mitophagic flux abolished the protective effects of Nano-Se. Collectively, these findings reveal that DON induces nephrotoxicity via the cuproptosis-mtROS-mitophagy axis and that Nano-Se ameliorates DON-induced renal inflammation by suppressing cuproptosis, reducing mtROS accumulation, and restoring mitophagic flux. This study provides a mechanistic basis for the use of Nano-Se as a potential therapeutic agent against mycotoxin-associated renal injury, with implications for environmental health risk assessment and livestock production. Download: Download high-res image (182KB) Download: Download full-size image
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Materials Today Bio
·
2026
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IF 11
Hui Zhang,Yuting Lu,Jingchun Wang,Yikai Ma,Yuanjin Sun,Shengzhong Rong,Xu Zhu,Yingxue Jin
Cuproptosis, a recently identified copper-dependent regulated cell death pathway driven by mitochondrial lipoylated protein aggregation, holds considerable promise for cancer therapy. Its clinical translation is constrained by off-target toxicity of free copper ions, inadequate mitochondria-targeted delivery and the immunosuppressive tumor microenvironment. We developed a hyaluronic acid-camouflaged, pH-responsive nanoplatform HACCR for mitochondria-targeted, cuproptosis-driven synergistic therapy and systemic antitumor immunity. The nanoplatform core relies on self-assembled architecture via π-π stacking between copper-metformin carbon dots and immune adjuvant R837, achieving high payload efficiencies 43.6% for CuMCDs and 35.2% for R837. CuMCDs synthesized via one-pot hydrothermal synthesis exhibit intrinsic mitochondria-targeting properties, facilitating precise copper delivery to cuproptosis initiation sites and amplifying pathway activation. They display efficient photothermal conversion under 808 nm laser irradiation, directly inducing tumor cell death while enhancing cuproptosis, chemodynamic therapy and immunogenic cell death. The hyaluronic acid-cinnamaldehyde micelle shell enables CD44-mediated tumor targeting and acidic tumor microenvironment-responsive payload release to mitigate off-target effects. In vitro and in vivo evaluations confirm effective cuproptosis induction, immunosuppressive tumor microenvironment reversal and enhanced dendritic cell maturation and T cell infiltration. Combined with anti-PD-L1 checkpoint blockade, HACCR achieves robust primary tumor eradication and distant metastasis inhibition with favorable systemic biosafety. This work establishes a versatile nanoplatform for cuproptosis-based synergistic cancer immunotherapy, offering insights for clinical translation of copper-dependent cell death strategies.
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Advanced Healthcare Materials
·
2026
·
IF 11
Ming Cheng,Jie Wu,Liru Heng,Yan Liu,Jinyu Yao,Tongtong Zhu,Yongming Zhu,Qiannan You,Zhubing Lei,Tong Wu,Wenfei Dong,Juan Yue,Yuanyuan Qin,Li Li
Glioblastoma (GBM) remains one of the most lethal intracranial malignancies due to its diffuse invasiveness and inevitable recurrence. Sonodynamic therapy (SDT) offers a noninvasive strategy for deep-tissue tumor ablation; however, its efficacy is often limited by rapid electron–hole recombination in conventional sonosensitizers, resulting in insufficient reactive oxygen species (ROS). In this study, a biomimetic nanosonosensitizer is rationally engineered via synergistic type II heterojunction interface construction and Cu─N coordination electronic activation. By anchoring Cu─N coordinated carbon dots (Cu-CDs) onto two-dimensional (2D) nanosheets, the compact heterojunction enables spatial charge separation, while Cu─N motifs act as kinetic promoters to accelerate interfacial electron transfer. This co-engineering strategy markedly enhances ultrasound (US) -triggered multi-ROS generation, leading to amplified oxidative stress. Biologically, intracellular copper overload triggers cuproptosis via lipoylated protein aggregation, whereas ROS burst induces PANoptosis-like cell death. Importantly, the synergistic death programs promote robust immunogenic cell death (ICD) with elevated Damage-associated molecular patterns (DAMPs) release/exposur, thereby activating antitumor immunity and contributing to enhanced therapeutic efficacy against GBM. This work provides new insights into the rational design of highly efficient sonosensitizers and offers new dimensions for precision SDT-based glioma sono-immunotherapy.
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FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Yangyang Lu,Yan Li,Xueying Sun,Xin Li,Shufen Zhao,Yuanyuan Fang,Wensheng Qiu,Cheng Luo,Weiwei Qi
Gastric cancer treatment remains challenging due to tumor heterogeneity and drug resistance. Cuproptosis, a novel form of cell death induced by excessive copper accumulation in mitochondria, is regulated by FDX1 and involves cytotoxic aggregation of lipoylated proteins such as DLAT. Given the markedly elevated copper levels observed in gastric cancer tissues, triggering cuproptosis represents a promising therapeutic strategy. Since cuproptosis strongly relies on active mitochondrial respiration, we hypothesized that mitochondrial uncoupling-which dissociates electron transport from oxidative phosphorylation by dissipating the proton gradient across the inner mitochondrial membrane, thereby enhancing respiratory activity-could sensitize gastric cancer cells to cuproptosis. In this study, we first established a cuproptosis model in gastric cancer cells using elesclomol combined with copper. We then systematically evaluated the enhancing effect of mitochondrial uncoupling on this process. Using the classical uncoupler FCCP and clinically relevant agents (niclosamide, nitazoxanide, and oxyclozanide), we confirmed mitochondrial uncoupling through membrane potential depolarization, an increased NAD + /NADH ratio, elevated oxygen consumption, and decreased ATP levels. Importantly, mitochondrial uncoupling significantly potentiated the cytotoxic effect of elesclomol-copper ion treatment in gastric cancer cells, which was closely associated with increased DLAT oligomerization. Mechanistic investigations revealed that mitochondrial uncoupling promotes cuproptosis susceptibility by upregulating DLAT and FDX1 protein expression and remodeling cellular metabolism. In summary, this study highlights the key role of mitochondrial uncoupling in amplifying cuproptosis and proposes a novel combination strategy based on metabolic intervention. These findings offer a new theoretical foundation and potential clinical translation prospects for gastric cancer treatment.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症代谢
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药理学
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Frontiers in Oncology
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2025
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IF 3.3
Xiao Liu,Honglin Qu,Jingmin Li,Xuhong Sun,Zhenlin Wang,Dong Wang,Xianyong Bai,Xiaoyan Li
Background Cuproptosis, a novel cell death pathway mediated by ferredoxin 1 (FDX1) and protein lipoylation, has emerged as a valuable target in cancer therapy. Although the findings of previous research have indicated a potential correlation between p53 and cuproptosis, the precise role and underlying mechanisms of p53 in cuproptosis, particularly within the context of hepatocellular carcinoma (HCC), remain unclear. Methods To evaluate cuproptosis, three HCC cell lines (HepG2, PLC/PRF/5, and Hep3B2.1-7) with distinct p53 statuses were treated with elesclomol-Cu. p53 overexpression/knockdown, siRNA-mediated ferredoxin reductase (FDXR)/FDX1 knockdown, and the p53 activators CP-31398 and nutlin-3 were employed to elucidate the associated molecular mechanisms. Cell viability, protein expression [FDX1, dihydrolipoyl transacetylase (DLAT), FDXR], and DLAT oligomerization were assessed via Cell Counting Kit-8 (CCK-8), western blotting, and immunofluorescence analyses. A PLC/PRF/5 xenograft mouse model was used to assess combined the therapeutic efficacy of elesclomol-Cu and CP-31398. Results Elesclomol-Cu triggered cuproptosis in HCC cells, as evidenced by a dose-dependent suppression of proliferation, FDX1 upregulation, DLAT oligomerization, and rescue by the copper chelator tetrathiomolybdate (TTM). p53 activation enhanced FDXR expression, promoting FDX1 upregulation and subsequent DLAT oligomerization, thereby sensitizing HCC cells to elesclomol-Cu, whereas FDXR knockdown reversed these effects, demonstrating its role in p53-mediated potentiation of cuproptosis sensitivity. In mutant p53-R249S cells, CP-31398 functioned synergistically with elesclomol-Cu to suppress proliferation. In vivo , elesclomol-Cu and CP-31398 combination therapy significantly reduced tumor growth and Ki67 expression whilst upregulating FDXR levels. Conclusions These findings revealed that p53 enhances elesclomol-Cu-induced cuproptosis in HCC via FDXR-mediated FDX1 upregulation. This study provides mechanistic insights into p53’s role in cuproptosis and may serve as a basis for targeting copper metabolism in therapeutic strategies for HCC.
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ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2025
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IF 3
Qun Gao,Qi Wang,Yanjiao Hu,Fangjie Xin,Jie Chen,Sha Yu,Xinli Chen,Qingqing Lv,Baoxia Cui,Jun Jiao,Xinlin Jiao
Purpose To investigate the impact of SIRT7 on the development of cervical cancer and its relationship with cuproptosis in cervical cancer. Method HeLa and SiHa cells were transfected with lentiviruses for SIRT7 overexpression and knockdown. The effects of SIRT7 on cervical cancer cell proliferation, apoptosis, invasion, and migration were analyzed using CCK8, plate cloning, flow cytometry, Transwell assays, and scratch assays. To verify the relationship between SIRT7 and cuproptosis, we utilized cuproptosis inhibitors and activators. Immunofluorescence, transmission electron microscope, flow cytometry, ELISA, and Western blot were used to analyze copper ion content, mitochondrial ultrastructure, cellular reactive oxygen species, mitochondrial membrane potential, pyruvate levels, cell viability and the cuproptosis-related proteins. Results SIRT7 enhanced the proliferation, migration, and invasion of HeLa and SiHa cells, inhibited apoptosis, and promoted cervical cancer growth. Knocking down SIRT7 caused cuproptosis of HeLa and SiHa cells, characterized by increased Cu 2+ content, disrupted mitochondrial structure, decreased membrane potential, elevated ROS production, and upregulation of cuproptosis-related proteins SLC31A1 and HSP70, and downregulation of FDX1, LIAS and DLAT. Low SIRT7 expression's effect on cuproptosis was reduced by TTM. SIRT7 overexpression inhibited cuproptosis, unlike SIRT7 knockdown. SIRT7 overexpression's inhibitory effect on cuproptosis is altered by rhSLC31A1. Conclusion SIRT7 was recognized as an oncogene in cervical cancer, which boosted cervical cancer cell proliferation and invasion, lowered intracellular copper levels, and prevented cuproptosis. SIRT7 downregulation triggered cuproptosis, inhibiting tumor cell growth.
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Biomolecules
·
2025
·Vol. 15
·期 6
·895
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IF 4.8
Yuhuan Wu,Ziyao Chang,Wenhao Wang,Chuanbin Wu,Xin Pan,Zhengwei Huang
Cuproptosis, a newly discovered copper-dependent programmed cell death pathway, represents a promising approach for anticancer therapy. However, the efficacy of cuproptosis critically depends on intracellular copper accumulation. Traditional copper ionophores have limited therapeutic efficacy due to their reliance on serum copper levels. Therefore, the development of novel copper ionophores to enhance intracellular copper levels is urgently needed. In this study, we targeted a melanoma model and pioneered the application of Bis(2-hydroxyethyl)dithiocarbamic acid copper(II) [Cu(HEDTC)2] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC)2exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)2@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC)2, as a novel copper ionophore, significantly enhanced the copper level in B16 melanoma cells. Upon cellular internalization, CS NM underwent degradation and released copper ions, which subsequently triggered cuproptosis by causing abnormal aggregation of mitochondrial lipoylated proteins. This study provides a new experimental foundation and potential therapeutic strategy for cuproptosis-based cancer treatment.
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Journal for ImmunoTherapy of Cancer
·
2025
·Vol. 13
·期 6
·e011472
·
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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Biomaterials Science
·
2025
·
IF 5.7
Yongguo Hu,Fang Zhang,Li-Li Chen,Xin-Yue Xu,Pei-Jie Zhang,Yong Li,Jin-Xuan Fan,Jia-Hua Zou,Yuan-Di Zhao
Cuproptosis is a copper-dependent programmed cell death triggered by mitochondrial dysfunction, offers significant anti-tumor potential but requires tumor-specific copper delivery to avoid systemic toxicity. Here, we developed a synergistic nanoplatform (Cu₂O@SiO₂-Ce6, CSC) integrating cuproptosis induction with photodynamic therapy (PDT). Cuprous oxide (Cu₂O) core was encapsulated in silicon dioxide and covalently linked to the photosensitizer Ce6. After accumulating in tumors regions via the EPR effect, CSC releases a surge of copper ions upon encountering the acidic tumor microenvironment and lysosomes. These ions induce mitochondrial cuproptosis by aggregating lipoylated TCA cycle proteins and depleting Fe-S cluster proteins. Concurrently, laser irradiation activates Ce6 to generate cytotoxic reactive oxygen species (ROS), actively disrupting tumor membranes. The experiments showed that the nanoplatform significantly enhanced the tumor cell killing effect and reduced the toxicity to normal tissues through a dual mechanism, which provided a new strategy for overcoming the drug resistance of PDT and the precise regulation of cuproptosis.
研究领域:
纳米医学
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肿瘤学
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生物化学
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光动力疗法
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细胞死亡机制
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靶向药物输送
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Shiwen Wang,Ying Shen,Binbin Hu,Qiping Wu,Nanzhou Wang,Zichao Wang,Zifeng Zhang,Yujie Li,Jianhui Jiang
Breast cancer therapy confronts dual challenges of metabolic plasticity-driven drug resistance and immunosuppression. To address this, we developed DCP-TPP, a therapeutic nanoplatform that integrates dysregulation of copper homeostasis and lipid metabolism for precise breast cancer therapy. Leveraging the overexpression of cluster of differentiation 36 (CD36) in breast cancer cells, DCP-TPP employs fatty acid camouflage (PCM) to deliver disulfiram (DSF) and photothermal Cu3BiS3 to cancer cells and features triphenylphosphonium (TPP) modification for targeted mitochondrial drug delivery. Near-infrared (NIR) irradiation triggers the phase transition of DCP-TPP’s outer layer, inducing spatiotemporal release of DSF to liberate copper ions from inert Cu3BiS3, thereby generating diethyldithiocarbamate–copper complex (CuET). This disrupts copper homeostasis and induces cuproptosis, which subsequently triggers S-acetyltransferase (DLAT) aggregation, impairing tricarboxylic acid (TCA) cycle flux, acetyl-CoA production, ATP citrate lyase (Acly)-dependent lipogenesis, and ultimately collapses mitochondrial oxidative phosphorylation. Multiomics profiling revealed oleic acid depletion, arachidonic acid oxidation, and glutathione exhaustion, collectively amplifying metabolic collapse. DCP-TPP-induced cell death enhanced dendritic cell (DC) activation and CD8+ T cell infiltration. In breast cancer models, DCP-TPP achieved 90.9% tumor suppression, with 60% of mice resisting rechallenge. By transforming lipid metabolic dependency into a therapeutic vulnerability and coupling it with copper ion toxicity, DCP-TPP offers a promising strategy for breast cancer therapy.
研究领域:
癌症生物学
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纳米医学
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免疫治疗
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代谢工程
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生物无机化学
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靶向药物递送
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