BIOMATERIALS
·
2025
·
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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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
Advanced Healthcare Materials
·
2025
·
IF 9.6
Hongyang Zhang,Rui-Hong Gong,Yu−Shan Lin,Tao Wang,Dou Luo,Jiahua Li,Li-Sha Shen,Wai-Yeung Wong,Sibao Chen,Guo-Qing Chen
Supramolecular polymers driven by the metal-ligand coordination possess reversible bonds, making them promising candidates for integrating the therapeutic functions of metal ions and small-molecule drugs, and subsequently releasing these components within cells after endocytosis. In this study, a kind of supramolecular polymer, SHICU, is developed, composed of Shikonin ligand and Cu(II) ion. Upon reduction by intracellular glutathione (GSH), SHICU dissociates to release Shikonin, Cu(II), and SHICU fragments. The released Shikonin and Cu(II) exhibit a synergistic antitumor effect through the reactive oxygen species (ROS)-dependent necrosis. Meanwhile, the released SHICU that remains structural integrity induces a distinct antitumor mechanism by triggering cuproptosis in tumor cells. This dual functionality, combining ROS-dependent necrosis and cuproptosis, highlights the potential of SHICU in advancing antitumor therapies, while the integration of supramolecular polymers with the emerging cell death mechanism of cuproptosis facilitates the development of innovative cancer drugs.
研究领域:
药理学
·
肿瘤学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Jianxiang Xu,Yingying Wang,Gareth R. Williams,Yilu Zheng,Yanyan Zhang,Tong Wang,Chengrong Du,Yu Wang,Ying-Li Wu,Li-Min Zhu
Excessive intracellular accumulation of metal ions results in metal-dependent programmed cell death, including ferroptosis and cuproptosis. However, cancer cells have defences against these processes, which allow them to resist therapy. Therefore, this work reports a laser-controlled cascade bioreactor based on gold and silica-coated Cu- and Mn-doped iron oxide nanocrystals (IONCs) loaded with the drug disulfiram (DSF). The resultant DSF/IONC@Au/MSN-TA nanoparticles (NPs) can deliver synergistic tumor metalloimmunotherapy through ferroptosis and cuproptosis. Under near-infrared laser (NIR) irradiation, DSF is released and chelates with Cu 2+ to form Cu + species in cancer cells, which leads to mitochondrial dysfunction via cuproptosis. The presence of gold nanodots on the DSF/IONC@Au/MSN-TA NPs allows them to consume intracellular glucose and sensitize cancer cells to cuproptosis. The DSF/IONC@Au/MSN-TA NPs induce ferroptosis via waterfall-like cyclic catalytic reactions, and iron ions released by the NPs consume glutathione (GSH), thereby enhancing sensitivity to cuproptosis and ferroptosis. The presence of manganese ions augments the efficacy of these processes and additionally allows imaging to be performed. A detailed physicochemical characterization of the NPs is reported, along with a series of assays to study the mechanisms of their biocatalytic activity. The NPs’ biocompatibility is also established, and they are found to be appropriate for bioimaging and theranostic applications. Our work thus offers an innovative route for targeted tumor metalloimmunotherapy.
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-20
·
IF 12.6
Gu Lina,Sun Ying,Bai Tingjie,Shao Sijie,Tang Shumin,Xue Panpan,Cai Wanlin,Qin Xian,Zeng Xuemei,Yan Shuangqian
Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death and subsequent antitumor immune responses. However, dysregulated copper metabolism in tumor cells maintains homeostatic copper balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed Cu ss OMEp, comprising a copper-based nanovector (Cu ss NV) that is PEGylated and loaded with omeprazole, a copper transporter inhibitor, to enhance tumor synergistic immunotherapy by promoting cuproptosis and ferroptosis. Cu ss NV is assembled from dithiodiglycolic acid and copper ions, exhibiting peroxidase, glutathione oxidase, and catalase-like activities, along with responsive degradability. This nanozyme alleviates tumor hypoxia by producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, and depletes glutathione. Additionally, omeprazole increases cellular copper concentration and oxidative stress by inhibiting the intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization and cuproptosis. In a breast tumor mouse model, Cu ss OMEp elicits robust antitumor immune responses, including dendritic cell maturation and T cell proliferation. When combined with PD-1 antibodies (αPD-1), Cu ss OMEp significantly inhibits tumor metastasis in bilateral and lung metastatic models. This work presents a functional nanozyme system as a promising strategy for synergistic tumor immunotherapy leveraging ferroptosis and cuproptosis Graphical abstract
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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产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2024
·
IF 6.9
Du Kaixuan,Luo Yongbo,Zhang Lei,Zeng Youmiao,Dai Yiheng,Ren Mengda,Pan Wenbang,Liu Yuanhao,Tian Fengyan,Zhou Lijie,Gu Chaohui
Cuproptosis, a cell death process caused by copper ions, is mediated by protein lipidation related to lipoic acid metabolism. There is a close connection between cuproptosis and the progression and prognosis of various tumors. Here, we identified lipoyltransferase 1 (LIPT1), a key gene related to cuproptosis, was downregulated in bladder cancer (BLCA) and was associated with unfavorable patient prognosis. Restoring the LIPT1 expression in BLCA cells suppressed the proliferation and promoted cuproptosis. Moreover, the consequences of RNA sequencing and Bodipy staining showed that the metabolic pathway mediated by LIPT1 inhibited the accumulation of lipid droplets in cells, disrupted endoplasmic reticulum (ER) homeostasis, and promoted cell apoptosis. Additionally, overexpression of LIPT1 not only repressed the proliferation rate of BLCA cells in vitro but also in vivo. Mechanistically, YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) promoted the degradation of LIPT1 mRNA in a m 6 A-dependent manner. In summary, these conclusions reveal that LIPT1 promotes cuprotosis and ER stress to inhibit the progression of BLCA, indicating that LIPT1 will provide a powerful treatment direction and drug target for treating BLCA.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Dongkai Jia,Lulu Liu,Wei Liu,Mengrou Geng,Jinjie Li,Haoqiang Guo,Ke Xu,Pinyi Liu,Ying Xin
Cuproptosis is a recently identified form of regulated cell death triggered by intracellular copper (Cu) overload. Diabetic conditions are characterized by disrupted Cu homeostasis. This study reveals a critical mechanistic link between the RNA methyltransferase WTAP and hypoxia-inducible factor-2α (HIF-2α) in promoting cardiomyocyte cuproptosis in diabetic cardiomyopathy (DCM). In both diabetic mouse hearts and high-fat/high-glucose plus Cu chloride-treated AC16 cardiomyocytes, elevated levels of WTAP and HIF-2α were observed alongside increased cuproptosis. Mechanistically, WTAP facilitates m 6 A-dependent upregulation of HIF-2α, which transcriptionally activates the divalent metal transporter 1 (DMT1). Enhanced DMT1 expression leads to intracellular Cu accumulation, subsequently inducing cuproptosis and driving DCM progression. Importantly, the clinically used agent dexmedetomidine (DEX) was found to alleviate DCM in vivo, at least in part, by suppressing DMT1 expression and thereby inhibiting cuproptosis. These findings identify the WTAP/HIF-2α/DMT1 axis as a key regulator of Cu overload and cuproptosis in DCM, highlighting its therapeutic potential.
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产品关联
DOI
PubMed
高影响因子
Cells
·
2025
·Vol. 14
·期 6
·391
·
IF 5.2
Yuhan Fu,Lirui Hou,Kai Han,Chong Zhao,Hongbo Hu,Shutao Yin
Background: Cuproptosis is a form of copper-dependent non-apoptotic cell death. Cancer cells that prefer to use aerobic glycolysis for energy generation are commonly insensitive to cuproptosis, which hinders its application for cancer treatment. Epigallocatechin gallate (EGCG) possesses diverse pharmacological activities. However, the association between EGCG and cuproptosis has not been studied. Methods: The cell viability, proliferation, and cuproptosis-related protein levels were detected to investigate whether EGCG enhances the sensitivity of HCC cells to cuproptosis. The intracellular copper level, related copper metabolism proteins, and gene expression were detected to explore the mechanisms. In addition, a nude mouse xenograft model was established to determine the effects of EGCG on cuproptosis in tumor tissues. Results: The combination of EGCG and copper ionophores significantly enhanced the mortality of HCC cells and heightened the sensitivity of HCC cells to cuproptosis. There was a notable reduction in the expression of copper export protein copper-transporting P-type ATPase (ATP7B). EGCG effectively suppressed metal regulatory transcription factor (MTF1) expression and subsequently hindered the transcriptional regulation of ATP7B. EGCG also facilitated the intratumoral accumulation of copper and augmented susceptibility to cuproptosis in vivo. Conclusions: EGCG can increase the sensitivity of hepatocellular carcinoma cells to cuproptosis by promoting intracellular copper accumulation through the MTF1/ATP7B axis.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Haoyu Yang,Xin Chen,Siqi Huang,Hongfang Dai,Zuowei Xiao,Jialong Fan,Honggang Zhang,Ke Du,Yan Qin
Ferroptosis and cuproptosis are two important new forms of ion-dependent cell death, whose processes can be inhibited by high levels of glutathione (GSH) within cells. Therefore, reducing GSH levels is a key strategy for inducing ferroptosis and cuproptosis. Herein, we successfully developed a curcumin (Cur) derivative, bisdemethylcurcumin (bm-Cur), as a novel GSH depletor that simultaneously induces ferroptosis and cuproptosis in hepatocellular carcinoma (HCC). The unique polyphenolic hydroxy structure and double α, β-unsaturated ketone structure of bm-Cur confers its potent GSH scavenging ability, which can effectively deplete GSH by simultaneously inhibiting GSH synthesis and directly consuming GSH levels, ultimately inducing ferroptosis and cuproptosis. Notably, bm-Cur can target mitochondria, induce mitochondrial lipid peroxidation and mitochondrial damage, thereby promoting ferroptosis and cuproptosis-mediated cell death, which demonstrates potential for anti-HCC activity in vitro and in vivo . Moreover, bm-Cur exhibited very low cytotoxicity, excellent biosafety and biocompatibility. In conclusion, this study suggests that bm-Cur may be a novel ferroptosis and cuproptosis activator with significant development potential for further application.
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Fangrong Tan,Yuandong Zeng,Donghua Dong,Yan Deng,Zhe Tang,LinGe Wang,Qianqian Yu
Cuproptosis offers a promising alternative to apoptosis-based cancer therapies but faces challenges, such as poor tumor drug accumulation, rapid clearance of copper ionophores, and high intracellular glutathione (GSH). Herein, we developed a GSH-responsive prodrug polymersome (PED@ICG) for copper-independent cuproptosis and synergistic photothermal therapy. Diethyldithiocarbamate (DTC) was covalently attached via disulfide bonds, ensuring a GSH-triggered release and intracellular GSH depletion. The amphiphilic polyprodrug formed stable polymersomes, and ICG coloading endowed imaging ability and NIR-activated photothermal heating. PED@ICG exhibited efficient cellular uptake through dynamin-mediated endocytosis, achieved deep tumor penetration, and selectively released DTC within the reductive tumor microenvironment. In vitro and in vivo studies demonstrated potent anticancer efficacy without the need for exogenous copper, while NIR irradiation further enhanced therapeutic outcomes through localized hyperthermia. This work offers a promising strategy for precise cuproptosis modulation and photothermal synergism, providing a clinically translatable nanoplatform for copper-independent tumor therapy.
研究领域:
纳米医学
·
癌症治疗
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药物递送
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光热治疗
·
细胞死亡机制
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-20
·
IF 12.6
Cai Hai,Xue Panpan,Liu Siyuan,Ma Yaxin,Zeng Xuemei,Yan Shuangqian,Xu Ning
Elevated squalene epoxidase (SQLE) levels in bladder cancer cells drive abnormal cholesterol accumulation, contributing to malignancy, invasion, and resistance to immunotherapy. Here, we introduce a hollow CuO nanoparticle-based nanotherapeutic, termed CuOTeDsP, which is PEGylated and co-loaded with SQLE inhibitor terbinafine and disulfiram, for enhanced bladder cancer therapy through cholesterol metabolism modulation. CuO nanoparticles exhibit peroxidase-, catalase-, and glutathione oxidase-like enzymatic activities, along with biodegradability, resulting in elevated oxidative stress, alleviation of hypoxia, and responsive therapeutic release. Terbinafine reduces cholesterol levels in cancer cells by inhibiting SQLE, downregulating the expression of ATP7A and PD-L1, thereby promoting cellular Cu 2+ accumulation and enhancing immune responses. Disulfiram further reacts with Cu 2+ to form lethal bis(diethyldithiocarbamate)-copper complexes. Mechanistic studies reveal that CuOTeDsP induces cell death through a combination of cuproptosis and apoptosis, while simultaneously eliciting robust immune responses. In synergy with PD-1 monoclonal antibody, CuOTeDsP achieves a high tumor inhibition rate of 70% in a mouse bladder cancer model. This work highlights an effective strategy for bladder cancer by leveraging cuproptosis-driven immunotherapy and provides insights into the design of advanced nanotherapeutics.
Section
Graphical abstract
研究领域:
纳米医学
·
癌症生物学
·
免疫学
·
代谢疾病
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药学
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产品关联
DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Ying Chen,Junyu Wang,Yaya Zheng,Jun Zhang,Juan Wang,Haoran Ye,Ling Tao,Yongchao Yao,Xinghong Luo,Yang Ding,Xiangchun Shen
Cuproptosis is a modality of mitochondrial cell death driven by the binding of excess copper ions to the lipoic acid residues of dihydrolipoamide S-acetyltransferase (DLAT) protein. However, copper levels are tightly regulated within cells. Herein, an oligocopper-loaded lipoic acid nanoparticle (Cu@TcNAs) is reported that can promote mitochondrial DLAT protein lipoylation and realize augmented cuproptosis therapy. This nanoparticle contains only 5.75% copper (mostly reported to be > 20%) and incorporates acetylgalactosamine as a target ligand. This targeted delivery increased cellular uptake of Cu@TcNAs and facilitated the degradation product of lipoic acid nanoparticles (dihydrolipoic acid, DHLA) to modify lysine residues of mitochondrial proteins, resulting in a 1.86- and 1.52-fold increase in lipoylated DLAT in HepG2 and 4T1 cells, respectively. These lipoylated DLATs enhance binding to released copper ions, promoting disulfide bond-dependent aggregation of lipoylated DLAT and causing cuproptosis in HepG2 and 4T1 cells with corresponding IC 50 values as low as 12.50 and 8.70 µg mL −1 , respectively. In vivo studies showed Cu@TcNAs at a copper dose of 0.27 mg kg −1 (mostly reported to be > 1.0 mg kg −1 ) achieved tumor inhibition rates of 74.32% and 84.87% in HepG2 and 4T1 tumor-bearing mice, respectively, demonstrating superior biosafety and significant clinical potential.
研究领域:
生物化学
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纳米技术
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肿瘤学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
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