MOLECULAR THERAPY
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2025
·
IF 12
Qian Yu,Ke Jiang,Siyu Ma,Quan Zheng,Serena Tondi,Chiara Reina,Berina Šabanović,Chenlei Wen,Baiyong Shen,Alexandra Aicher,Haiyun Song,Yinxing Ma,Christopher Heeschen
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, partly due to cancer stem cells (CSCs) that drive progression and treatment resistance. We explored the therapeutic potential of inducing cuproptosis, a copper-dependent regulated cell death, in CSC-enriched PDAC models. Using human and murine PDAC models, we evaluated elesclomol, a copper transport enhancer. Elesclomol alone had minimal effects; combined with copper chloride (CuCl 2 ), it significantly and irreversibly reduced CSC phenotypes without affecting non-transformed cells. Mechanistically, only the combination raised intracellular copper ions 2–4-fold, decreased iron–sulfur cluster proteins, and caused fatty acylated DLAT accumulation in mitochondria, triggering cuproptosis, particularly in CSCs. It also selectively inhibited copper-dependent antioxidant SOD1 in PDAC cells, impairing oxidative stress defense and sensitizing them to copper-induced death. To enhance clinical relevance, CuCl 2 was replaced with hollow mesoporous copper sulfide nanoparticles releasing copper ions. Either combined with or loaded with elesclomol, these nanoparticles similarly increased copper levels and inhibited PDAC spheroid formation. In vivo , in aggressive immunocompetent murine PDAC models, this nanoparticle-based treatment significantly improved gemcitabine response. These findings identify nanoparticle-mediated cuproptosis induction, combined with standard chemotherapy, as an innovative CSC-targeting strategy to improve PDAC outcomes, offering new hope for PDAC patients.
研究领域:
肿瘤学
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分子生物学
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癌症治疗学
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纳米医学
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细胞死亡机制
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DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Xufeng Lu,Xiaodong Chen,Chengyin Lin,Yongdong Yi,Shengsheng Zhao,Bingzi Zhu,Wenhai Deng,Xiang Wang,Zuoliang Xie,Shangrui Rao,Zhonglin Ni,Tao You,Liyi Li,Yingpeng Huang,Xiangyang Xue,Yaojun Yu,Weijian Sun,Xian Shen
The induction of cuproptosis, a recently identified form of copper-dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu 2+ ) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis-inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu 2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis-mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death-1 (PD-1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis-mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.
研究领域:
肿瘤学
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纳米技术
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免疫疗法
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
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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产品关联
DOI
PubMed
高影响因子
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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PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 22
·e71250
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IF 4.2
Jian Zhao,Yili Chen,Di Lu,Yuanyuan Zeng,Jianjun Li,Jianjie Zhu,Zhe Lei,Jian-an Huang,Zeyi Liu
Copper ionophores such as elesclomol (ES) have been identified as effective agents capable of inducing cuproptosis, a recently characterized form of regulated cell death driven by copper overload. However, the interplay among copper toxicity, endoplasmic reticulum stress, and metabolic rewiring in lung adenocarcinoma (LUAD) remains poorly understood. Here, we demonstrate that ES selectively transports extracellular copper into human LUAD cells, inducing ER stress and upregulating PCK2, a gluconeogenic enzyme with context-dependent roles in cancer. RNA sequencing and functional assays revealed that PCK2 elevation under copper overload affects glucose metabolism and lipid metabolism to suppress malignant phenotypes. Clinically, high PCK2 expression is correlated with favorable prognosis in LUAD patients, as evidenced by analyses of public datasets. Knocking down PCK2 paradoxically increased proliferation and cell motility, suggesting that PCK2 plays a tumor-suppressive role under copper stress. KRAS G12D transgenic mice-derived lung cancer organoids were used to validate the in vitro therapeutic effects of ES + Cu by regulating PCK2 expression. In vivo experiments revealed that ES inhibited tumor growth and upregulated PCK2. Taking together, our findings reveal that the ES-ER stress-PCK2 axis is a critical mediator of copper-induced metabolic disruption, providing a rationale for targeting cuproptosis pathways in LUAD therapy. Graphical Schematic diagram of copper-induced cell death in LUAD. Elesclomol, as a copper ionophore, promotes copper influx into LUAD cells. This copper influx leads to cellular copper overload. Copper overload induces ER stress in LUAD cells. ER stress upregulates PCK2, which in turn inhibits the tricarboxylic acid (TCA) cycle. Collectively, these pathways orchestrate the cellular responses to excessive copper levels in LUAD cells, highlighting the complex interplay between copper homeostasis, metabolic reprogramming, and cell death mechanisms.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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细胞死亡机制
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药理学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Hangyi Wu,Zhenhai Zhang,Yanni Cao,Yuhan Hu,Yi Li,Lanyi Zhang,Xinyi Cao,Haitong Wen,Youwen Zhang,Huixia Lv,Xin Jin
Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half-life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES-Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high-level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu 2+ -stimulated Fenton-like reaction together with CA-stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli-dissociation of ECPCP, forming a positive feedback therapy loop against tumor self-alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application.
研究领域:
药学
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纳米技术
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肿瘤学
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免疫治疗
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Wenchang Yang,Yaxin Wang,Yongzhou Huang,Jiaxian Yu,Tao Wang,Chengguo Li,Lei Yang,Peng Zhang,Liang Shi,Yuping Yin,Kaixiong Tao,Ruidong Li
Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas of investigation, particularly in cancers. The present study aimed to explore the role of cuproptosis in colorectal cancer progression. The genetic alterations of cuproptosis in colon cancer were evaluated using a database. MTT assays, colony formation, and flow cytometry were used to examine the effect of elesclomol-Cu and 4-Octyl itaconate (4-OI) on colorectal cancer cell and oxaliplatin-resistant cell viability. The anti-tumor effect of elesclomol with 4-OI was verified in vivo assay. The results showed that FDX1, SDHB, DLAT, and DLST genes were more highly expressed in normal tissues than those in primary tumor tissues. Patients with high expressions of these genes in tumor tissues had a better prognosis. Using MTT assay and colony formation analysis, elesclomol-Cu pulse treatment showed significant inhibition of cell viability in HCT116, LoVo, and HCT116-R cells. In addition, flow cytometry revealed elesclomol-Cu significantly promoted apoptosis. Tetrathiomolybdate, a copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy- D -glucose, a glucose metabolism inhibitor, sensitized cuproptosis. Furthermore, galactose further promoted cuproptosis. Interestingly, 4-OI significantly enhanced cuproptosis which was irrelevant to ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis was inhibited by 4-OI through GAPDH, one of the key enzymes of glycolysis, sensitizing cuproptosis. Meanwhile, FDX1 knockdown weakened the ability of 4-OI to promote cuproptosis. In vivo experiments, 4-OI with elesclomol-Cu showed better anti-tumor effects. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.
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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癌症研究
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产品关联
DOI
PubMed
高影响因子
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