Ferroptosis is an iron-dependent,excessive lipid peroxidation-driven form of regulated cell death.The core mechanisms of ferroptosis include lipid peroxidation cascade,System X_(c)^(−)-glutathioneglutathione peroxidas...Ferroptosis is an iron-dependent,excessive lipid peroxidation-driven form of regulated cell death.The core mechanisms of ferroptosis include lipid peroxidation cascade,System X_(c)^(−)-glutathioneglutathione peroxidase 4 axis,iron and lipid metabolism chaos,the NAD(P)Hferroptosis suppressor protein 1—ubiquinone axis,and GTP cyclohydrolase 1 tetrahydrobiopterin-dihydrofolate reductase axis.Cuproptosis is triggered by copper ions and involves ferredoxin 1-mediated aggregation of lipoylated proteins,differing fundamentally from ferroptosis.Both ferroptosis and cuproptosis exhibit dual roles(promote or inhibit)in cancers.And the sensitivity of different cancer types to ferroptosis varies,which may depend on special metabolic signatures(e.g.,E-cadherin loss causes epithelial–mesenchymal transition,making tumors gain resistance to ferroptosis)and expression of antioxidant defense regulators(e.g.,high expression of Acyl-CoA synthetase long-chain family member 4 and lncFASA make tumors easily sensitive).At present,traditional Chinese herbal medicine,combination therapy,and nano-delivery technology correlated with ferroptosis are being hotly studied by researchers in order to realize clinical translation of ferroptosis.In this review,we have summarized the core mechanisms of ferroptosis,ferroptosis differences from cuproptosis,its impact on cancers,and its translational implications in cancer therapy,helping readers quickly get the new information and horizons on them.展开更多
There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which a...There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which are resistant to conventional chemotherapy.Here,we established a nano strategy to kill glioma cells and CSCs,combining carfilzomib and bis(diethyldithiocarbamate)copper.The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis.The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site.This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.展开更多
The therapeutic efficacy of cuproptosis,ferroptosis,and apoptosis is hindered by inadequate intracellular copper and iron levels,hypoxia,and elevated glutathione(GSH)expression in tumor cells.Thermoelectric technology...The therapeutic efficacy of cuproptosis,ferroptosis,and apoptosis is hindered by inadequate intracellular copper and iron levels,hypoxia,and elevated glutathione(GSH)expression in tumor cells.Thermoelectric technology is an emerging frontier in medical therapy that aims to achieve efficient thermal and electrical transport characteristics within a narrow thermal range for biological systems.Here,we systematically constructed biodegradable Cu_(2)MnS_(3-x)-PEG/glucose oxidase(MCPG)with sulfur vacancies(S_(V))using photothermoelectric catalysis(PTEC),photothermal-enhanced enzyme catalysis,and starvation therapy.This triggers GSH consumption and disrupts intracellular redox homeostasis,leading to immunogenic cell death.Under 1064 nm laser irradiation,MCPG enriched with S_(V),owing to doping,generates a local temperature gradient that activates PTEC and produces toxic reactive oxygen species(ROS).Hydroxyl radicals and oxygen are generated through peroxide and catalase-like processes.Increased oxygen levels alleviate tumor hypoxia,whereas hydrogen peroxide production from glycometabolism provides sufficient ROS for a cascade catalytic reaction,establishing a self-reinforcing positive mechanism.Density functional theory calculations demonstrated that vacancy defects effectively enhanced enzyme catalytic activity.Multimodal imaging-guided synergistic therapy not only damages tumor cells,but also elicits an antitumor immune response to inhibit tumor metastasis.This study offers novel insights into the cuproptosis/ferroptosis/apoptosis pathways of Cu-based PTEC nanozymes.展开更多
Background:Primary liver cancer poses a significant global health burden,with projections indicating a surpassing of one million cases by 2025.Cuproptosis,a copper-dependent mechanism of cell death,plays a crucial rol...Background:Primary liver cancer poses a significant global health burden,with projections indicating a surpassing of one million cases by 2025.Cuproptosis,a copper-dependent mechanism of cell death,plays a crucial role in the pathogenesis,progression,and prognosis of various cancers,including hepatocellular carcinoma(HCC).Purpose:This study aimed to develop a prognostic model for HCC based on cuproptosis-related genes,utilizing clinical data and gene expression profiles from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Materials and Methods:Clinical features and gene expression data of HCC patients were collected from publicly available databases.Patients from TCGA were randomly divided into training and testing sets,and Lasso Cox regression was applied to develop a predictive model using cuproptosis-related genes.Results:The analysis identified Copper Metabolism Domain Containing 1(COMMD1)as a potential prognostic marker for HCC,with deletion of this gene impacting disease progression.Cellular functional experiments validated the role of COMMD1 in HCC.Conclusions:COMMD1 emerges as a promising candidate for HCC treatment,with implications for prognosis prediction and therapeutic targeting.展开更多
Background Myocardial infarction(MI)and postmyocardial remodeling are the most common causes of heart failure worldwide and seriously affect the quality of life and prognosis of patients.Dapagliflozin,a sodium glucose...Background Myocardial infarction(MI)and postmyocardial remodeling are the most common causes of heart failure worldwide and seriously affect the quality of life and prognosis of patients.Dapagliflozin,a sodium glucose cotransporter 2(SGLT2)inhibitor,is a novel class of hypoglycemic drug that has been proven to have cardiovascular protective effects.However,the underlying mechanisms by which dapagliflozin affects MI have yet to be elucidated.Methods An MI mouse model was created by ligating the left anterior descending branch of the coronary artery.Hematoxylin‒eosin(HE)and Masson’s trichrome(Masson)staining were used to assess myocardial damage.The levels of fibrosis-related and cuproptosis-related markers were assessed via Western blot analysis.A hypoxia-induced cardiomyocyte fibrosis model was constructed in vitro.The DCFH-DA probe was used to measure the levels of reactive oxygen species(ROS),and flow cytometry was used to identify cell apoptosis.Results Dapagliflozin improved heart function,ameliorated fibrosis in the myocardium,and alleviated myocardial injury.Moreover,dapagliflozin reduced the copper ion concentration and ROS accumulation and inhibited the expression of cuproptosis-related markers.Dapagliflozin suppressed the expression of HIF-1α/TGF-βsignal and the overexpression of HIF-1αeffectively reversed the dapagliflozin-mediated myocardial protective effects.Conclusion Dapagliflozin reduced myocardial fibrosis by suppressing HIF-1α/TGF-β-mediated cuproptosis.展开更多
BACKGROUND Colorectal cancer(CRC)is a major global health burden.B cell CLL/lymphoma 10(BCL10),a key component of the caspase recruitment domain protein-BCL10-mucosa-associated lymphoid tissue lymphoma paracaspase com...BACKGROUND Colorectal cancer(CRC)is a major global health burden.B cell CLL/lymphoma 10(BCL10),a key component of the caspase recruitment domain protein-BCL10-mucosa-associated lymphoid tissue lymphoma paracaspase complexes,is upregulated in CRC and associated with poor patient prognosis,suggesting its potential role in CRC development and progression.Cuproptosis,a novel form of programmed cell death,has emerged as a promising therapeutic strategy for cancer.AIM To explore the role of BCL10 in regulating the sensitivity of CRC cells to cuproptosis.METHODS A series of in vitro and in vivo experiments were conducted using CRC cell lines and CRC mouse models to evaluate the effects of BCL10 on CRC cell proliferation,migration,invasion,and sensitivity to copper-induced cell death.Mechanistic studies were performed to elucidate the underlying molecular pathways.RESULTS BCL10 promoted CRC cell proliferation,migration,and invasion,while its knockdown had the opposite effects.BCL10 also influenced the sensitivity of CRC cells to cuproptosis,with BCL10 overexpression enhancing resistance and its knockdown increasing sensitivity.The mechanism involved BCL10 modulating the expression of DLAT,a key protein in the copper-induced cell death pathway,through activation of the nuclear factor kappa-B(NF-κB)signaling pathway.CONCLUSION BCL10 promotes CRC growth and regulates the sensitivity of CRC cells to cuproptosis by activating the NF-κB signaling pathway and modulating DLAT expression.These findings provide a molecular basis for developing BCL10-targeted therapies for CRC.展开更多
AIM:To investigate cuproptosis-related molecular and immune infiltration in age-related macular degeneration(AMD)development and establish a predictive model.METHODS:The expression profiles of cuproptosisrelated genes...AIM:To investigate cuproptosis-related molecular and immune infiltration in age-related macular degeneration(AMD)development and establish a predictive model.METHODS:The expression profiles of cuproptosisrelated genes and immune signature in AMD based on the microarray dataset GSE29801 were analyzed.A total of 142 AMD samples were used to identify the cuproptosisrelated differentially expressed genes(Cu-DEGs),together with the immune cell infiltration.To further refine the list of potential genes for AMD diagnosis,three machine learning techniques were used,and an external dataset were applied for confirming the accuracy of the predictive performance.Reverse transcription polymerase chain reaction(RT-PCR)were also performed to examine the level of mRNA of hub genes.The activated immune responses and Cu-DEGs were assessed between AMD and controls.RESULTS:Six genes,including ATP7A,DBT,VEGFA,UBE2D3,CP,SLC31A1,were screened as cuproptosissignature in AMD via three machine learning methods.Next,SLC31A1 and VEGFA was selected as hub genes by performance evaluation in an external dataset GSE160011,further analysis showed that SLC31A1 and VEGFA were associated with pathways related to immune signaling and immune function,which were then observed in relation to infiltrating immune cells.Finally,the mRNA expression levels of SLC31A1 and VEGFA were significantly higher in laser induced choroidal neovascularization(CNV)group than in control group detected by RT-PCR.CONCLUSION:In this study,the possible relationship between cuproptosis and AMD is expounded systematically.A predictive model is developed to assess the risk of cuproptosis-related genes and their clinical prognostic value in AMD patients.展开更多
In the study published in the World Journal of Clinical Cases by Xu et al,the expression profiles of cuproptosis-related genes in esophageal cancer and their prognostic significance were investigated.Cuproptosis,a nov...In the study published in the World Journal of Clinical Cases by Xu et al,the expression profiles of cuproptosis-related genes in esophageal cancer and their prognostic significance were investigated.Cuproptosis,a novel form of copperdependent cell death,has garnered significant attention in cancer research due to its mechanism closely linked to mitochondrial metabolism and protein lipoylation.This research systematically analyzed the prognostic value of cuproptosisrelated genes by integrating multi-omics data from 151 esophageal cancer and normal tissue samples.The study identified pyruvate dehydrogenase A1(PDHA1)as an independent prognostic marker for esophageal cancer.Patients with high PDHA1 expression exhibited significantly lower overall survival rates.Functional enrichment analysis further revealed that cuproptosis drives tumor progression by regulating mitochondrial tricarboxylic acid cycle activity and metabolic reprogramming of glucose metabolism.Long non-coding RNAs(LncRNAs),RNA molecules exceeding 200 nucleotides that do not encode proteins,have been extensively examined in this context.In specific tumor types,certain LncRNAs play a role in regulating cuproptosis by influencing copper ion metabolism,transport,and associated signaling pathways.These LncRNAs may interact with pivotal genes involved in cuproptosis,modulating their expression levels and participating in the regulation of this process.Current research has concentrated on the correlation between cuproptosis-linked LncRNAs and diverse cancers.A comprehensive investigation into the connections among LncRNAs,cuproptosis-related genes,pathways,and their impact on tumor drug resistance holds promise for precise cancer treatment and prognosis assessment.展开更多
Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment.According to a recently published study in Science,copper death(cuproptosis)occurs when intrac...Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment.According to a recently published study in Science,copper death(cuproptosis)occurs when intracellular copper is overloaded,triggering aggregation of lipidated mitochondrial proteins and Fe–S cluster proteins.This intriguing phenomenon is triggered by the instability of copper ions.Understanding the molecular mechanisms behind cuproptosis and its associated genes,as identified by Tsvetkov,including ferredoxin 1,lipoic acid synthase,lipoyltransferase 1,dihydrolipid amide dehydrogenase,dihydrolipoamide transacetylase,pyruvate dehydrogenaseα1,pyruvate dehydrogenaseβ,metallothionein,glutaminase,and cyclin-dependent kinase inhibitor 2A,may open new avenues for cancer therapy.Here,we provide a new understanding of the role of copper death and related genes in cancer.展开更多
Various therapeutic strategies have been developed to overcome ovarian cancer.However,the prognoses resulting from these strategies are still unclear.In the present work,we screened 54 small molecule compounds approve...Various therapeutic strategies have been developed to overcome ovarian cancer.However,the prognoses resulting from these strategies are still unclear.In the present work,we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells.Among these,we identified disulfiram(DSF),an old alcohol-abuse drug,as a potential inducer of cell death in ovarian cancer.Mechanistically,DSF treatment significantly reduced the expression of the anti-apoptosis marker Bcell lymphoma/leukemia-2(Bcl-2)and increase the expression of the apoptotic molecules Bcl2 associated X(Bax)and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis.Furthermore,DSF is a newly identified effective copper ionophore,thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment.Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins(biomarkers of cuproptosis).In vivo,DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model.Thus,the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.展开更多
Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess ca...Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.展开更多
Objective Cuproptosis is a novel cell death pathway that was newly discovered in early 2022.However,cuproptosis is still in its infancy in many respects and warrants further research in hepatocellular carcinoma(HCC).T...Objective Cuproptosis is a novel cell death pathway that was newly discovered in early 2022.However,cuproptosis is still in its infancy in many respects and warrants further research in hepatocellular carcinoma(HCC).This study aimed to analyze the mechanism of cuprptosis in HCC.Methods Herein,the tumor microenvironment infiltration landscape of molecular subtypes was illustrated using GSVA,ssGSEA,TIMER,CIBERSORT,and ESTIMATE algorithms based on the expression profile of cuproptosis-related genes(CRGs)from TCGA and GEO databases.Then,the least absolute shrinkage and selection operator regression method was applied to construct a cuproptosis signature to quantify the cuproptosis profile of HCC.Further,we explored the expression of three hub CRGs in cell lines and clinical patient tissues of HCC by Western blotting,qRT-PCR and immunohistochemistry.Finally,we examined the function of dihydrolipoamide S-acetyltransferase(DLAT)in cuproptosis in HCC by loss-of-function strategy,Western blotting and CCK8 assay.Results Three distinct molecular subtypes were identified.Cluster 2 had the greatest infiltration of immune cells with best prognosis.The cuproptosis signature was indicative of tumor subtype,immunity,and prognosis for HCC,and specifically,a low cuproptosis score foreshadowed good prognosis.DLAT was highly expressed in liver cancer cell lines and HCC tissues and positively correlated with clinical stage and grade.We also found that potent copper ionophore elesclomol could induce cuproptosis in a copper-dependent manner.Selective Cu^(++)chelator ammonium tetrathiomolybdate and downregulating DLAT expression by siRNA could effectively inhibit cuproptosis.Conclusion Cuproptosis and DLAT as a promising biomarker could help to determine the prognosis of HCC and may offer novel insights for effective treatment.展开更多
Cuproptosis,a novel mechanism of programmed cell death,has not been fully explored in the context of spermatogenic cells.Thisstudy investigated the potential involvement of cuproptosis in spermatogenic cell death usin...Cuproptosis,a novel mechanism of programmed cell death,has not been fully explored in the context of spermatogenic cells.Thisstudy 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 withsodium 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.Micesubjected to copper overload exhibited a disruption in copper homeostasis.Additionally,significant upregulated expression of keycuproptosis factors was accompanied by a significant rise in the rates of testicular tissue cell apoptosis.Immunohistochemicalanalysis revealed the presence of ferredoxin 1(Fdx1)in Sertoli cells,Leydig cells,and spermatogenic cells at various stages oftesticular development,and the Fdx1-positive staining area was significantly increased in copper-overloaded mice.Mitochondrialdysfunction and decreased adenosine triphosphate levels were also observed,further implicating mitochondrial damage undercuproptosis.Further analyses revealed pathological lesions and blood−testis barrier destruction in the testicular tissue,accompaniedby decreased sperm concentration and motility,in copper-overloaded mice.In summary,our results indicate that copper-overloadedmice 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 initialexperimental evidence for the occurrence of cuproptosis in the testis.展开更多
BACKGROUND Cuproptosis has recently been considered a novel form of programmed cell death.To date,long-chain non-coding RNAs(lncRNAs)crucial to the regulation of this process remain unelucidated.AIM To identify lncRNA...BACKGROUND Cuproptosis has recently been considered a novel form of programmed cell death.To date,long-chain non-coding RNAs(lncRNAs)crucial to the regulation of this process remain unelucidated.AIM To identify lncRNAs linked to cuproptosis in order to estimate patients'prognoses for hepatocellular carcinoma(HCC).METHODS Using RNA sequence data from The Cancer Genome Atlas Live Hepatocellular Carcinoma(TCGA-LIHC),a co-expression network of cuproptosis-related genes and lncRNAs was constructed.For HCC prognosis,we developed a cuproptosisrelated lncRNA signature(CupRLSig)using univariate Cox,lasso,and multivariate Cox regression analyses.Kaplan-Meier analysis was used to compare overall survival among high-and low-risk groups stratified by median CupRLSig risk score.Furthermore,comparisons of functional annotation,immune infiltration,somatic mutation,tumor mutation burden(TMB),and pharmacologic options were made between high-and low-risk groups.RESULTS Three hundred and forty-three patients with complete follow-up data were recruited in the analysis.Pearson correlation analysis identified 157 cuproptosis-related lncRNAs related to 14 cuproptosis genes.Next,we divided the TCGA-LIHC sample into a training set and a validation set.In univariate Cox regression analysis,27 LncRNAs with prognostic value were identified in the training set.After lasso regression,the multivariate Cox regression model determined the identified risk equation as follows:Risk score=(0.2659×PICSAR expression)+(0.4374×FOXD2-AS1 expression)+(-0.3467×AP001065.1 expression).The CupRLSig high-risk group was associated with poor overall survival(hazard ratio=1.162,95%CI=1.063-1.270;P<0.001)after the patients were divided into two groups depending upon their median risk score.Model accuracy was further supported by receiver operating characteristic and principal component analysis as well as the validation set.The area under the curve of 0.741 was found to be a better predictor of HCC prognosis as compared to other clinicopathological variables.Mutation analysis revealed that high-risk combinations with high TMB carried worse prognoses(median survival of 30 mo vs 102 mo of low-risk combinations with low TMB group).The low-risk group had more activated natural killer cells(NK cells,P=0.032 by Wilcoxon rank sum test)and fewer regulatory T cells(Tregs,P=0.021)infiltration than the high-risk group.This finding could explain why the low-risk group has a better prognosis.Interestingly,when checkpoint gene expression(CD276,CTLA-4,and PDCD-1)and tumor immune dysfunction and rejection(TIDE)scores are considered,highrisk patients may respond better to immunotherapy.Finally,most drugs commonly used in preclinical and clinical systemic therapy for HCC,such as 5-fluorouracil,gemcitabine,paclitaxel,imatinib,sunitinib,rapamycin,and XL-184(cabozantinib),were found to be more efficacious in the low-risk group;erlotinib,an exception,was more efficacious in the high-risk group.CONCLUSION The lncRNA signature,CupRLSig,constructed in this study is valuable in prognostic estimation of HCC.Importantly,CupRLSig also predicts the level of immune infiltration and potential efficacy of tumor immunotherapy.展开更多
BACKGROUND Worldwide,gastric cancer(GC)is a common lethal solid malignancy with a poor prognosis.Cuproptosis is a novel type of cell death mediated by protein lipoylation and may be related to GC prognosis.AIM To offe...BACKGROUND Worldwide,gastric cancer(GC)is a common lethal solid malignancy with a poor prognosis.Cuproptosis is a novel type of cell death mediated by protein lipoylation and may be related to GC prognosis.AIM To offer new insights to predict GC prognosis and provide multiple therapeutic targets related to cuproptosis-related genes(CRGs)for future therapy.METHODS We collected data from several public data portals,systematically estimated the expression level and prognostic values of CRGs in GC samples,and investigated related mechanisms using public databases and bioinformatics.RESULTS Our results revealed that FDX1,LIAS,and MTF1 were differentially expressed in GC samples and exhibited important prognostic significance in The Cancer Genome Atlas(TCGA)cohort.We constructed a nomogram model for overall survival and disease-specific survival prediction and validated it via calibration plots.Mecha-nistically,immune cell infiltration and DNA methylation prominently affected the survival time of GC patients.Moreover,protein-protein interaction network,KEGG pathway and gene ontology enrichment analyses demonstrated that FDX1,LIAS,MTF1 and related proteins play key roles in the tricarboxylic acid cycle and cuproptosis.Gene Expression Omnibus database validation showed that the expression levels of FDX1,LIAS,and MTF1 were consistent with those in the TCGA cohort.Top 10 perturbagens has been filtered CONCLUSION In conclusion,FDX1,LIAS,and MTF1 could serve as potential prognostic biomarkers for GC patients and provide novel targets for immunotarget therapy.展开更多
BACKGROUND Over the past few years,research into the pathogenesis of colon cancer has progressed rapidly,and cuproptosis is an emerging mode of cellular apoptosis.Exploring the relationship between colon cancer and cu...BACKGROUND Over the past few years,research into the pathogenesis of colon cancer has progressed rapidly,and cuproptosis is an emerging mode of cellular apoptosis.Exploring the relationship between colon cancer and cuproptosis benefits in identifying novel biomarkers and even improving the outcome of the disease.AIM To look at the prognostic relationship between colon cancer and the genes associated with cuproptosis and the immune system in patients.The main purpose was to assess whether reasonable induction of these biomarkers reduces mortality among patients with colon cancers.METHOD Data obtained from The Cancer Genome Atlas and Gene Expression Omnibus and the Genotype-Tissue Expression were used in differential analysis to explore differential expression genes associated with cuproptosis and immune activation.The least absolute shrinkage and selection operator and Cox regression algorithm was applied to build a cuproptosis-and immune-related combination model,and the model was utilized for principal component analysis and survival analysis to observe the survival and prognosis of the patients.A series of statistically meaningful transcriptional analysis results demonstrated an intrinsic relationship between cuproptosis and the micro-environment of colon cancer.RESULTS Once prognostic characteristics were obtained,the CDKN2A and DLAT genes related to cuproptosis were strongly linked to colon cancer:The first was a risk factor,whereas the second was a protective factor.The finding of the validation analysis showed that the comprehensive model associated with cuproptosis and immunity was statistically significant.Within the component expressions,the expressions of HSPA1A,CDKN2A,and UCN3 differed markedly.Transcription analysis primarily reflects the differential activation of related immune cells and pathways.Furthermore,genes linked to immune checkpoint inhibitors were expressed differently between the subgroups,which may reveal the mechanism of worse prognosis and the different sensitivities of chemotherapy.CONCLUSION The prognosis of the high-risk group evaluated in the combined model was poorer,and cuproptosis was highly correlated with the prognosis of colon cancer.It is possible that we may be able to improve patients’prognosis by regulating the gene expression to intervene the risk score.展开更多
Objective To identify cuproptosis-and ferroptosis-related genes involved in nonalcoholic fatty liver disease and to determine the diagnostic value of hub genes.Methods The gene expression dataset GSE89632 was retrieve...Objective To identify cuproptosis-and ferroptosis-related genes involved in nonalcoholic fatty liver disease and to determine the diagnostic value of hub genes.Methods The gene expression dataset GSE89632 was retrieved from the Gene Expression Omnibus database to identify differentially expressed genes(DEGs)between the non-alcoholic steatohepatitis(NASH)group and the healthy group using the'limma'package in R software and weighted gene co-expression network analysis.Gene ontology,kyoto encyclopedia of genes and genomes pathway,and single-sample gene set enrichment analyses were performed to identify functional enrichment of DEGs.Ferroptosis-and cuproptosis-related genes were obtained from the FerrDb V2 database and available literatures,respectively.A combined signature for cuproptosis-and ferroptosis-related genes,called CRF,was constructed using the STRING database.Hub genes were identified by overlapping DEGs,WGCNA-derived key genes,and combined signature CRF genes,and validated using the GSE109836 and GSE227714 datasets and real-time quantitative polymerase chain reaction.A nomogram of NASH diagnostic model was established utilizing the'rms'package in R software based on the hub genes,and the diagnostic value of hub genes was assessed using receiver operating characteristic curve analysis.In addition,immune cell infiltration in NASH versus healthy controls was examined using the CIBERSORT algorithm.The relationships among various infiltrated immune cells were explored with Spearman's correlation analysis.Results Analysis of GSE89632 identified 236 DEGs between the NASH group and the healthy group.WGCNA highlighted 8 significant modules and 11,095 pivotal genes,of which 330 genes constituted CRF.Intersection analysis identified IL6,IL1B,JUN,NR4A1,and PTGS2 as hub genes.The hub genes were all downregulated in the NASH group,and this result was further verified by the NASH validation dataset and real-time quantitative polymerase chain reaction.Receiver operating characteristic curve analysis confirmed the diagnostic efficacy of these hub genes with areas under the curve of 0.985,0.941,1.000,0.967,and 0.985,respectively.Immune infiltration assessment revealed that gamma delta T cells,M1 macrophages,M2 macrophages,and resting mast cells were predominantly implicated.Conclusion Our investigation underscores the significant association of cuproptosis-and ferroptosis-related genes,specifically IL6,IL1B,JUN,NR4A1,and PTGS2,with NASH.These findings offer novel insights into the pathogenesis of NASH,potentially guiding future diagnostic and therapeutic strategies.展开更多
Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o ...Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o rganisms,plants and animals through direct or indirect exposure.However,the current understanding of the toxicity of copper is rather limited.Copper overload can perturb intracellular homeostasis and induce oxidative stress and e ven cell death.Recently,cuproptosis has been identified as a copper-dependent form of cell death induced by o xidative stress in mitochondria.We uncover here that zinc transporter 1(ZNT1)is an important regulator involved in cuproptosis.Firstly,we established the copper overload-induced cell death model with the overexpression of copper importer SLC31A1 in HeLa cells.Using this model,we conducted unbiased genome-wide CRISPR-Cas9 screens in cells treated with copper.Our results revealed a significant enrichment of ZNT1 gene in both library A and library B plasmids.Knocking out of ZNT1 in HeLa cells notably prevented cuproptosis.Subsequent knockout of metal transcription factor 1(MTF1)in ZNT1-deficient cells nearly abolished their ability to resist copper-induced cell death.However,overexpression of metallothionein 1X(MT1X)in the double-knockout cells could p artially restored the resistance to cuproptosis by loss of MTF1.Mechanistically,knockout of ZNT1 could promote MT1X expression by activating MTF1.As a consequence,the interaction between MT1X and copper was e nhanced,reducing the flow of copper into mitochondria and eliminating mitochondria damage.Taken together,this study reveals the important role of ZNT1 in cuproptosis and shows MTF1-MT1X axis mediated resistance to c uproptosis.Moreover,our study will help to understand the regulatory mechanism of cellular and systemic copper homeostasis under copper overload,and present insights into novel treatments for damages caused by both genetic copper overload diseases and environmental copper contamination.展开更多
BACKGROUND Esophageal cancer is one of the most common malignant tumors of the digestive system,with a 5-year survival rate of 15%to 50%.Cuproptosis,a unique kind of cell death driven by protein lipoylation,is strongl...BACKGROUND Esophageal cancer is one of the most common malignant tumors of the digestive system,with a 5-year survival rate of 15%to 50%.Cuproptosis,a unique kind of cell death driven by protein lipoylation,is strongly connected to mitochondrial metabolism.The clinical implications of cuproptosis-related genes in esophageal cancer,however,are mainly unknown.AIM To identify cuprotosis-related genes that are differentially expressed in esophageal cancer and investigate their prognostic significance.METHODS With|log fold change|>1 and false discovery rate<0.05 as criteria,the Wilcox test was used to evaluate the differentially expressed genes between 151 tumor tissues and 151 normal esophageal tissues.Cuproptosis-related genes were selected to be linked with prognosis using univariate Cox regression analysis.Genes were separated into high-and low-expression groups based on their cutoff value of gene expression,and the correlation between the two groups and overall survival or progression-free survival was investigated using the log-rank test.The C-index,calibration curve,and receiver operator characteristic(ROC)curve were used to assess a nomogram containing clinicopathological characteristics and cuproptosis-related genes.RESULTS Pyruvate dehydrogenase A1(PDHA1)was found to be highly correlated with prognosis in univariate Cox regression analysis(hazard ratio=22.96,95%confidence interval=3.09-170.73;P=0.002).According to Kaplan-Meier survival curves,low expression of PDHA1 was associated with a better prognosis(log-rank P=0.0007).There was no significant correlation between PDHA1 expression and 22 different types of immune cells.Tumor necrosis factor superfamily member 15(TNFSF15)(P=3.2×10^(-6);r=0.37),TNFRSF14(P=8.1×10^(-8);r=0.42),H long terminal repeat-associating 2(P=6.0×10^(-8);r=0.42)and galectin 9(P=3.1×10^(-6);r=0.37)were all found to be considerably greater in the high PDHA1 expression group,according to an analysis of genes related to 47 immunological checkpoints.The low PDHA1 expression group had significantly lower levels of cluster of differentiation 44(CD44)(P=0.00028;R=-0.29),TNFRSF18(P=1.2×10^(-5);R=-0.35),programmed cell death 1 ligand 2(P=0.0032;R=-0.24),CD86(P=0.018;R=-0.19),and CD40(P=0.0047;R=-0.23),and the differences were statistically significant.We constructed a prognostic nomogram incorporating pathological type,tumor-node-metastasis stage,and PDHA1 expression,and the C-index,calibration curve,and ROC curve revealed that the nomogram’s predictive performance was good.CONCLUSION Cuproptosis-related genes can be used as a prognostic predictor for esophageal cancer patients,providing novel insights into cancer treatment.展开更多
基金supported by National Natural Science Foundation(82272695)the Key Program of Natural Science Foundation of Zhejiang Province(LZ23H160004)National Undergraduate Training Program for Innovation and Entrepreneurship,Zhejiang Xinmiao Talents Program,China.
文摘Ferroptosis is an iron-dependent,excessive lipid peroxidation-driven form of regulated cell death.The core mechanisms of ferroptosis include lipid peroxidation cascade,System X_(c)^(−)-glutathioneglutathione peroxidase 4 axis,iron and lipid metabolism chaos,the NAD(P)Hferroptosis suppressor protein 1—ubiquinone axis,and GTP cyclohydrolase 1 tetrahydrobiopterin-dihydrofolate reductase axis.Cuproptosis is triggered by copper ions and involves ferredoxin 1-mediated aggregation of lipoylated proteins,differing fundamentally from ferroptosis.Both ferroptosis and cuproptosis exhibit dual roles(promote or inhibit)in cancers.And the sensitivity of different cancer types to ferroptosis varies,which may depend on special metabolic signatures(e.g.,E-cadherin loss causes epithelial–mesenchymal transition,making tumors gain resistance to ferroptosis)and expression of antioxidant defense regulators(e.g.,high expression of Acyl-CoA synthetase long-chain family member 4 and lncFASA make tumors easily sensitive).At present,traditional Chinese herbal medicine,combination therapy,and nano-delivery technology correlated with ferroptosis are being hotly studied by researchers in order to realize clinical translation of ferroptosis.In this review,we have summarized the core mechanisms of ferroptosis,ferroptosis differences from cuproptosis,its impact on cancers,and its translational implications in cancer therapy,helping readers quickly get the new information and horizons on them.
基金sponsored by Shanghai Education Commission Major Project(2017-01-07-00-07-E00052)National Natural Science Foundation of China(No.81773657)+1 种基金Shanghai Sailing Program(No.20YF1404500)Scientific Research Foundation of Huashan Hospital,Fudan University(No.2019QD012).
文摘There remain several intractable challenges for chemotherapy in glioma treatment,including the blood-brain barrier(BBB),blood-brain tumor barrier(BBTB),and tumor heterogeneity caused by cancer stem cells(CSCs),which are resistant to conventional chemotherapy.Here,we established a nano strategy to kill glioma cells and CSCs,combining carfilzomib and bis(diethyldithiocarbamate)copper.The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis.The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site.This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.
基金supported by the National Natural Science Foundation of China(NSFC 52002091,U22A20347,and 52102344)Heilongjiang Natural Science Foundation Project of Outstanding Youth Project(YQ2023B005)+1 种基金China Postdoctoral Science Foundation(2023T160154)the Fundamental Research Funds for the Central Universities。
文摘The therapeutic efficacy of cuproptosis,ferroptosis,and apoptosis is hindered by inadequate intracellular copper and iron levels,hypoxia,and elevated glutathione(GSH)expression in tumor cells.Thermoelectric technology is an emerging frontier in medical therapy that aims to achieve efficient thermal and electrical transport characteristics within a narrow thermal range for biological systems.Here,we systematically constructed biodegradable Cu_(2)MnS_(3-x)-PEG/glucose oxidase(MCPG)with sulfur vacancies(S_(V))using photothermoelectric catalysis(PTEC),photothermal-enhanced enzyme catalysis,and starvation therapy.This triggers GSH consumption and disrupts intracellular redox homeostasis,leading to immunogenic cell death.Under 1064 nm laser irradiation,MCPG enriched with S_(V),owing to doping,generates a local temperature gradient that activates PTEC and produces toxic reactive oxygen species(ROS).Hydroxyl radicals and oxygen are generated through peroxide and catalase-like processes.Increased oxygen levels alleviate tumor hypoxia,whereas hydrogen peroxide production from glycometabolism provides sufficient ROS for a cascade catalytic reaction,establishing a self-reinforcing positive mechanism.Density functional theory calculations demonstrated that vacancy defects effectively enhanced enzyme catalytic activity.Multimodal imaging-guided synergistic therapy not only damages tumor cells,but also elicits an antitumor immune response to inhibit tumor metastasis.This study offers novel insights into the cuproptosis/ferroptosis/apoptosis pathways of Cu-based PTEC nanozymes.
文摘Background:Primary liver cancer poses a significant global health burden,with projections indicating a surpassing of one million cases by 2025.Cuproptosis,a copper-dependent mechanism of cell death,plays a crucial role in the pathogenesis,progression,and prognosis of various cancers,including hepatocellular carcinoma(HCC).Purpose:This study aimed to develop a prognostic model for HCC based on cuproptosis-related genes,utilizing clinical data and gene expression profiles from The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Materials and Methods:Clinical features and gene expression data of HCC patients were collected from publicly available databases.Patients from TCGA were randomly divided into training and testing sets,and Lasso Cox regression was applied to develop a predictive model using cuproptosis-related genes.Results:The analysis identified Copper Metabolism Domain Containing 1(COMMD1)as a potential prognostic marker for HCC,with deletion of this gene impacting disease progression.Cellular functional experiments validated the role of COMMD1 in HCC.Conclusions:COMMD1 emerges as a promising candidate for HCC treatment,with implications for prognosis prediction and therapeutic targeting.
基金supported by Fujian Provincial Natural Science Foundation of China(No.2022J011489 and No.2023J011876)Startup Fund for Scientific Research of Fujian Medical University(No.2021QH1210).
文摘Background Myocardial infarction(MI)and postmyocardial remodeling are the most common causes of heart failure worldwide and seriously affect the quality of life and prognosis of patients.Dapagliflozin,a sodium glucose cotransporter 2(SGLT2)inhibitor,is a novel class of hypoglycemic drug that has been proven to have cardiovascular protective effects.However,the underlying mechanisms by which dapagliflozin affects MI have yet to be elucidated.Methods An MI mouse model was created by ligating the left anterior descending branch of the coronary artery.Hematoxylin‒eosin(HE)and Masson’s trichrome(Masson)staining were used to assess myocardial damage.The levels of fibrosis-related and cuproptosis-related markers were assessed via Western blot analysis.A hypoxia-induced cardiomyocyte fibrosis model was constructed in vitro.The DCFH-DA probe was used to measure the levels of reactive oxygen species(ROS),and flow cytometry was used to identify cell apoptosis.Results Dapagliflozin improved heart function,ameliorated fibrosis in the myocardium,and alleviated myocardial injury.Moreover,dapagliflozin reduced the copper ion concentration and ROS accumulation and inhibited the expression of cuproptosis-related markers.Dapagliflozin suppressed the expression of HIF-1α/TGF-βsignal and the overexpression of HIF-1αeffectively reversed the dapagliflozin-mediated myocardial protective effects.Conclusion Dapagliflozin reduced myocardial fibrosis by suppressing HIF-1α/TGF-β-mediated cuproptosis.
基金Supported by the National Natural Science Foundation of China,No.82073299Special Project for Health Research Talents of Jilin Province,No.2023SCZ25.
文摘BACKGROUND Colorectal cancer(CRC)is a major global health burden.B cell CLL/lymphoma 10(BCL10),a key component of the caspase recruitment domain protein-BCL10-mucosa-associated lymphoid tissue lymphoma paracaspase complexes,is upregulated in CRC and associated with poor patient prognosis,suggesting its potential role in CRC development and progression.Cuproptosis,a novel form of programmed cell death,has emerged as a promising therapeutic strategy for cancer.AIM To explore the role of BCL10 in regulating the sensitivity of CRC cells to cuproptosis.METHODS A series of in vitro and in vivo experiments were conducted using CRC cell lines and CRC mouse models to evaluate the effects of BCL10 on CRC cell proliferation,migration,invasion,and sensitivity to copper-induced cell death.Mechanistic studies were performed to elucidate the underlying molecular pathways.RESULTS BCL10 promoted CRC cell proliferation,migration,and invasion,while its knockdown had the opposite effects.BCL10 also influenced the sensitivity of CRC cells to cuproptosis,with BCL10 overexpression enhancing resistance and its knockdown increasing sensitivity.The mechanism involved BCL10 modulating the expression of DLAT,a key protein in the copper-induced cell death pathway,through activation of the nuclear factor kappa-B(NF-κB)signaling pathway.CONCLUSION BCL10 promotes CRC growth and regulates the sensitivity of CRC cells to cuproptosis by activating the NF-κB signaling pathway and modulating DLAT expression.These findings provide a molecular basis for developing BCL10-targeted therapies for CRC.
文摘AIM:To investigate cuproptosis-related molecular and immune infiltration in age-related macular degeneration(AMD)development and establish a predictive model.METHODS:The expression profiles of cuproptosisrelated genes and immune signature in AMD based on the microarray dataset GSE29801 were analyzed.A total of 142 AMD samples were used to identify the cuproptosisrelated differentially expressed genes(Cu-DEGs),together with the immune cell infiltration.To further refine the list of potential genes for AMD diagnosis,three machine learning techniques were used,and an external dataset were applied for confirming the accuracy of the predictive performance.Reverse transcription polymerase chain reaction(RT-PCR)were also performed to examine the level of mRNA of hub genes.The activated immune responses and Cu-DEGs were assessed between AMD and controls.RESULTS:Six genes,including ATP7A,DBT,VEGFA,UBE2D3,CP,SLC31A1,were screened as cuproptosissignature in AMD via three machine learning methods.Next,SLC31A1 and VEGFA was selected as hub genes by performance evaluation in an external dataset GSE160011,further analysis showed that SLC31A1 and VEGFA were associated with pathways related to immune signaling and immune function,which were then observed in relation to infiltrating immune cells.Finally,the mRNA expression levels of SLC31A1 and VEGFA were significantly higher in laser induced choroidal neovascularization(CNV)group than in control group detected by RT-PCR.CONCLUSION:In this study,the possible relationship between cuproptosis and AMD is expounded systematically.A predictive model is developed to assess the risk of cuproptosis-related genes and their clinical prognostic value in AMD patients.
基金Supported by The National Health Commission's Key Laboratory of Gastrointestinal Tumor Diagnosis and Treatment for the Year 2022,National Health Commission's Master's and 6/12 Doctoral/Postdoctoral Fund Project,No.NHCDP2022001Gansu Provincial People's Hospital Doctoral Supervisor Training Project,No.22GSSYA-3.
文摘In the study published in the World Journal of Clinical Cases by Xu et al,the expression profiles of cuproptosis-related genes in esophageal cancer and their prognostic significance were investigated.Cuproptosis,a novel form of copperdependent cell death,has garnered significant attention in cancer research due to its mechanism closely linked to mitochondrial metabolism and protein lipoylation.This research systematically analyzed the prognostic value of cuproptosisrelated genes by integrating multi-omics data from 151 esophageal cancer and normal tissue samples.The study identified pyruvate dehydrogenase A1(PDHA1)as an independent prognostic marker for esophageal cancer.Patients with high PDHA1 expression exhibited significantly lower overall survival rates.Functional enrichment analysis further revealed that cuproptosis drives tumor progression by regulating mitochondrial tricarboxylic acid cycle activity and metabolic reprogramming of glucose metabolism.Long non-coding RNAs(LncRNAs),RNA molecules exceeding 200 nucleotides that do not encode proteins,have been extensively examined in this context.In specific tumor types,certain LncRNAs play a role in regulating cuproptosis by influencing copper ion metabolism,transport,and associated signaling pathways.These LncRNAs may interact with pivotal genes involved in cuproptosis,modulating their expression levels and participating in the regulation of this process.Current research has concentrated on the correlation between cuproptosis-linked LncRNAs and diverse cancers.A comprehensive investigation into the connections among LncRNAs,cuproptosis-related genes,pathways,and their impact on tumor drug resistance holds promise for precise cancer treatment and prognosis assessment.
基金Supported by Scientific Research Project of Hunan Education Department,No.21A0054.
文摘Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment.According to a recently published study in Science,copper death(cuproptosis)occurs when intracellular copper is overloaded,triggering aggregation of lipidated mitochondrial proteins and Fe–S cluster proteins.This intriguing phenomenon is triggered by the instability of copper ions.Understanding the molecular mechanisms behind cuproptosis and its associated genes,as identified by Tsvetkov,including ferredoxin 1,lipoic acid synthase,lipoyltransferase 1,dihydrolipid amide dehydrogenase,dihydrolipoamide transacetylase,pyruvate dehydrogenaseα1,pyruvate dehydrogenaseβ,metallothionein,glutaminase,and cyclin-dependent kinase inhibitor 2A,may open new avenues for cancer therapy.Here,we provide a new understanding of the role of copper death and related genes in cancer.
基金funded by Guangzhou Scienceand Information Bureau Item of China(Grant No.201904010013)by Natural Science Foundation of Guangdong Province of China(Grant No.2018A0303130180).
文摘Various therapeutic strategies have been developed to overcome ovarian cancer.However,the prognoses resulting from these strategies are still unclear.In the present work,we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells.Among these,we identified disulfiram(DSF),an old alcohol-abuse drug,as a potential inducer of cell death in ovarian cancer.Mechanistically,DSF treatment significantly reduced the expression of the anti-apoptosis marker Bcell lymphoma/leukemia-2(Bcl-2)and increase the expression of the apoptotic molecules Bcl2 associated X(Bax)and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis.Furthermore,DSF is a newly identified effective copper ionophore,thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment.Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins(biomarkers of cuproptosis).In vivo,DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model.Thus,the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.
基金supported by grants from the National Natural Science Foundation of China(No.81971891,No.82172196 and No.82372507)the Natural Science Foundation of Hunan Province(No.2023JJ40804)the Key Laboratory of Emergency and Trauma of Ministry of Education(Hainan Medical University,No.KLET-202210).
文摘Copper is an essential trace element,and plays a vital role in numerous physiological processes within the human body.During normal metabolism,the human body maintains copper homeostasis.Copper deficiency or excess can adversely affect cellular function.Therefore,copper homeostasis is stringently regulated.Recent studies suggest that copper can trigger a specific form of cell death,namely,cuproptosis,which is triggered by excessive levels of intracellular copper.Cuproptosis induces the aggregation of mitochondrial lipoylated proteins,and the loss of iron-sulfur cluster proteins.In neurodegenerative diseases,the pathogenesis and progression of neurological disorders are linked to copper homeostasis.This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases.This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.
基金This research was financially supported by grants from the National Natural Science Foundation of China(No.82073095,No.82172938 and No.81670554)Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University(No.CXPY2020042).
文摘Objective Cuproptosis is a novel cell death pathway that was newly discovered in early 2022.However,cuproptosis is still in its infancy in many respects and warrants further research in hepatocellular carcinoma(HCC).This study aimed to analyze the mechanism of cuprptosis in HCC.Methods Herein,the tumor microenvironment infiltration landscape of molecular subtypes was illustrated using GSVA,ssGSEA,TIMER,CIBERSORT,and ESTIMATE algorithms based on the expression profile of cuproptosis-related genes(CRGs)from TCGA and GEO databases.Then,the least absolute shrinkage and selection operator regression method was applied to construct a cuproptosis signature to quantify the cuproptosis profile of HCC.Further,we explored the expression of three hub CRGs in cell lines and clinical patient tissues of HCC by Western blotting,qRT-PCR and immunohistochemistry.Finally,we examined the function of dihydrolipoamide S-acetyltransferase(DLAT)in cuproptosis in HCC by loss-of-function strategy,Western blotting and CCK8 assay.Results Three distinct molecular subtypes were identified.Cluster 2 had the greatest infiltration of immune cells with best prognosis.The cuproptosis signature was indicative of tumor subtype,immunity,and prognosis for HCC,and specifically,a low cuproptosis score foreshadowed good prognosis.DLAT was highly expressed in liver cancer cell lines and HCC tissues and positively correlated with clinical stage and grade.We also found that potent copper ionophore elesclomol could induce cuproptosis in a copper-dependent manner.Selective Cu^(++)chelator ammonium tetrathiomolybdate and downregulating DLAT expression by siRNA could effectively inhibit cuproptosis.Conclusion Cuproptosis and DLAT as a promising biomarker could help to determine the prognosis of HCC and may offer novel insights for effective treatment.
基金supported by the National Natural Science Foundation ofChina(No.81973647 and No.82274325)the Chengdu Municipal HealthCommission(No.2023215).
文摘Cuproptosis,a novel mechanism of programmed cell death,has not been fully explored in the context of spermatogenic cells.Thisstudy 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 withsodium 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.Micesubjected to copper overload exhibited a disruption in copper homeostasis.Additionally,significant upregulated expression of keycuproptosis factors was accompanied by a significant rise in the rates of testicular tissue cell apoptosis.Immunohistochemicalanalysis revealed the presence of ferredoxin 1(Fdx1)in Sertoli cells,Leydig cells,and spermatogenic cells at various stages oftesticular development,and the Fdx1-positive staining area was significantly increased in copper-overloaded mice.Mitochondrialdysfunction and decreased adenosine triphosphate levels were also observed,further implicating mitochondrial damage undercuproptosis.Further analyses revealed pathological lesions and blood−testis barrier destruction in the testicular tissue,accompaniedby decreased sperm concentration and motility,in copper-overloaded mice.In summary,our results indicate that copper-overloadedmice 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 initialexperimental evidence for the occurrence of cuproptosis in the testis.
基金Supported by the National Key Clinical Discipline,the Basic and Applied Basic Research Fund Project of Guangdong Province,No.2021A1515410004 and No.2019A1515011200National Natural Science Foundation of China,No.81973858 and No.82172790Science and Technology Plan Project of Qingyuan City,No.2019A028.
文摘BACKGROUND Cuproptosis has recently been considered a novel form of programmed cell death.To date,long-chain non-coding RNAs(lncRNAs)crucial to the regulation of this process remain unelucidated.AIM To identify lncRNAs linked to cuproptosis in order to estimate patients'prognoses for hepatocellular carcinoma(HCC).METHODS Using RNA sequence data from The Cancer Genome Atlas Live Hepatocellular Carcinoma(TCGA-LIHC),a co-expression network of cuproptosis-related genes and lncRNAs was constructed.For HCC prognosis,we developed a cuproptosisrelated lncRNA signature(CupRLSig)using univariate Cox,lasso,and multivariate Cox regression analyses.Kaplan-Meier analysis was used to compare overall survival among high-and low-risk groups stratified by median CupRLSig risk score.Furthermore,comparisons of functional annotation,immune infiltration,somatic mutation,tumor mutation burden(TMB),and pharmacologic options were made between high-and low-risk groups.RESULTS Three hundred and forty-three patients with complete follow-up data were recruited in the analysis.Pearson correlation analysis identified 157 cuproptosis-related lncRNAs related to 14 cuproptosis genes.Next,we divided the TCGA-LIHC sample into a training set and a validation set.In univariate Cox regression analysis,27 LncRNAs with prognostic value were identified in the training set.After lasso regression,the multivariate Cox regression model determined the identified risk equation as follows:Risk score=(0.2659×PICSAR expression)+(0.4374×FOXD2-AS1 expression)+(-0.3467×AP001065.1 expression).The CupRLSig high-risk group was associated with poor overall survival(hazard ratio=1.162,95%CI=1.063-1.270;P<0.001)after the patients were divided into two groups depending upon their median risk score.Model accuracy was further supported by receiver operating characteristic and principal component analysis as well as the validation set.The area under the curve of 0.741 was found to be a better predictor of HCC prognosis as compared to other clinicopathological variables.Mutation analysis revealed that high-risk combinations with high TMB carried worse prognoses(median survival of 30 mo vs 102 mo of low-risk combinations with low TMB group).The low-risk group had more activated natural killer cells(NK cells,P=0.032 by Wilcoxon rank sum test)and fewer regulatory T cells(Tregs,P=0.021)infiltration than the high-risk group.This finding could explain why the low-risk group has a better prognosis.Interestingly,when checkpoint gene expression(CD276,CTLA-4,and PDCD-1)and tumor immune dysfunction and rejection(TIDE)scores are considered,highrisk patients may respond better to immunotherapy.Finally,most drugs commonly used in preclinical and clinical systemic therapy for HCC,such as 5-fluorouracil,gemcitabine,paclitaxel,imatinib,sunitinib,rapamycin,and XL-184(cabozantinib),were found to be more efficacious in the low-risk group;erlotinib,an exception,was more efficacious in the high-risk group.CONCLUSION The lncRNA signature,CupRLSig,constructed in this study is valuable in prognostic estimation of HCC.Importantly,CupRLSig also predicts the level of immune infiltration and potential efficacy of tumor immunotherapy.
基金Supported by The Key Scientific and Technological Projects of Ningbo,No.2021Z133.
文摘BACKGROUND Worldwide,gastric cancer(GC)is a common lethal solid malignancy with a poor prognosis.Cuproptosis is a novel type of cell death mediated by protein lipoylation and may be related to GC prognosis.AIM To offer new insights to predict GC prognosis and provide multiple therapeutic targets related to cuproptosis-related genes(CRGs)for future therapy.METHODS We collected data from several public data portals,systematically estimated the expression level and prognostic values of CRGs in GC samples,and investigated related mechanisms using public databases and bioinformatics.RESULTS Our results revealed that FDX1,LIAS,and MTF1 were differentially expressed in GC samples and exhibited important prognostic significance in The Cancer Genome Atlas(TCGA)cohort.We constructed a nomogram model for overall survival and disease-specific survival prediction and validated it via calibration plots.Mecha-nistically,immune cell infiltration and DNA methylation prominently affected the survival time of GC patients.Moreover,protein-protein interaction network,KEGG pathway and gene ontology enrichment analyses demonstrated that FDX1,LIAS,MTF1 and related proteins play key roles in the tricarboxylic acid cycle and cuproptosis.Gene Expression Omnibus database validation showed that the expression levels of FDX1,LIAS,and MTF1 were consistent with those in the TCGA cohort.Top 10 perturbagens has been filtered CONCLUSION In conclusion,FDX1,LIAS,and MTF1 could serve as potential prognostic biomarkers for GC patients and provide novel targets for immunotarget therapy.
文摘BACKGROUND Over the past few years,research into the pathogenesis of colon cancer has progressed rapidly,and cuproptosis is an emerging mode of cellular apoptosis.Exploring the relationship between colon cancer and cuproptosis benefits in identifying novel biomarkers and even improving the outcome of the disease.AIM To look at the prognostic relationship between colon cancer and the genes associated with cuproptosis and the immune system in patients.The main purpose was to assess whether reasonable induction of these biomarkers reduces mortality among patients with colon cancers.METHOD Data obtained from The Cancer Genome Atlas and Gene Expression Omnibus and the Genotype-Tissue Expression were used in differential analysis to explore differential expression genes associated with cuproptosis and immune activation.The least absolute shrinkage and selection operator and Cox regression algorithm was applied to build a cuproptosis-and immune-related combination model,and the model was utilized for principal component analysis and survival analysis to observe the survival and prognosis of the patients.A series of statistically meaningful transcriptional analysis results demonstrated an intrinsic relationship between cuproptosis and the micro-environment of colon cancer.RESULTS Once prognostic characteristics were obtained,the CDKN2A and DLAT genes related to cuproptosis were strongly linked to colon cancer:The first was a risk factor,whereas the second was a protective factor.The finding of the validation analysis showed that the comprehensive model associated with cuproptosis and immunity was statistically significant.Within the component expressions,the expressions of HSPA1A,CDKN2A,and UCN3 differed markedly.Transcription analysis primarily reflects the differential activation of related immune cells and pathways.Furthermore,genes linked to immune checkpoint inhibitors were expressed differently between the subgroups,which may reveal the mechanism of worse prognosis and the different sensitivities of chemotherapy.CONCLUSION The prognosis of the high-risk group evaluated in the combined model was poorer,and cuproptosis was highly correlated with the prognosis of colon cancer.It is possible that we may be able to improve patients’prognosis by regulating the gene expression to intervene the risk score.
文摘Objective To identify cuproptosis-and ferroptosis-related genes involved in nonalcoholic fatty liver disease and to determine the diagnostic value of hub genes.Methods The gene expression dataset GSE89632 was retrieved from the Gene Expression Omnibus database to identify differentially expressed genes(DEGs)between the non-alcoholic steatohepatitis(NASH)group and the healthy group using the'limma'package in R software and weighted gene co-expression network analysis.Gene ontology,kyoto encyclopedia of genes and genomes pathway,and single-sample gene set enrichment analyses were performed to identify functional enrichment of DEGs.Ferroptosis-and cuproptosis-related genes were obtained from the FerrDb V2 database and available literatures,respectively.A combined signature for cuproptosis-and ferroptosis-related genes,called CRF,was constructed using the STRING database.Hub genes were identified by overlapping DEGs,WGCNA-derived key genes,and combined signature CRF genes,and validated using the GSE109836 and GSE227714 datasets and real-time quantitative polymerase chain reaction.A nomogram of NASH diagnostic model was established utilizing the'rms'package in R software based on the hub genes,and the diagnostic value of hub genes was assessed using receiver operating characteristic curve analysis.In addition,immune cell infiltration in NASH versus healthy controls was examined using the CIBERSORT algorithm.The relationships among various infiltrated immune cells were explored with Spearman's correlation analysis.Results Analysis of GSE89632 identified 236 DEGs between the NASH group and the healthy group.WGCNA highlighted 8 significant modules and 11,095 pivotal genes,of which 330 genes constituted CRF.Intersection analysis identified IL6,IL1B,JUN,NR4A1,and PTGS2 as hub genes.The hub genes were all downregulated in the NASH group,and this result was further verified by the NASH validation dataset and real-time quantitative polymerase chain reaction.Receiver operating characteristic curve analysis confirmed the diagnostic efficacy of these hub genes with areas under the curve of 0.985,0.941,1.000,0.967,and 0.985,respectively.Immune infiltration assessment revealed that gamma delta T cells,M1 macrophages,M2 macrophages,and resting mast cells were predominantly implicated.Conclusion Our investigation underscores the significant association of cuproptosis-and ferroptosis-related genes,specifically IL6,IL1B,JUN,NR4A1,and PTGS2,with NASH.These findings offer novel insights into the pathogenesis of NASH,potentially guiding future diagnostic and therapeutic strategies.
文摘Industrial activities such as smelting emissions,mineral combustion and industrial wastewater discharge might lead to copper pollution in the environment.This kind of copper pollution has harmful effects on aquatic o rganisms,plants and animals through direct or indirect exposure.However,the current understanding of the toxicity of copper is rather limited.Copper overload can perturb intracellular homeostasis and induce oxidative stress and e ven cell death.Recently,cuproptosis has been identified as a copper-dependent form of cell death induced by o xidative stress in mitochondria.We uncover here that zinc transporter 1(ZNT1)is an important regulator involved in cuproptosis.Firstly,we established the copper overload-induced cell death model with the overexpression of copper importer SLC31A1 in HeLa cells.Using this model,we conducted unbiased genome-wide CRISPR-Cas9 screens in cells treated with copper.Our results revealed a significant enrichment of ZNT1 gene in both library A and library B plasmids.Knocking out of ZNT1 in HeLa cells notably prevented cuproptosis.Subsequent knockout of metal transcription factor 1(MTF1)in ZNT1-deficient cells nearly abolished their ability to resist copper-induced cell death.However,overexpression of metallothionein 1X(MT1X)in the double-knockout cells could p artially restored the resistance to cuproptosis by loss of MTF1.Mechanistically,knockout of ZNT1 could promote MT1X expression by activating MTF1.As a consequence,the interaction between MT1X and copper was e nhanced,reducing the flow of copper into mitochondria and eliminating mitochondria damage.Taken together,this study reveals the important role of ZNT1 in cuproptosis and shows MTF1-MT1X axis mediated resistance to c uproptosis.Moreover,our study will help to understand the regulatory mechanism of cellular and systemic copper homeostasis under copper overload,and present insights into novel treatments for damages caused by both genetic copper overload diseases and environmental copper contamination.
基金Supported by the Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine Talent Boosting Plan,No.SY-XKZT-2020-3007.
文摘BACKGROUND Esophageal cancer is one of the most common malignant tumors of the digestive system,with a 5-year survival rate of 15%to 50%.Cuproptosis,a unique kind of cell death driven by protein lipoylation,is strongly connected to mitochondrial metabolism.The clinical implications of cuproptosis-related genes in esophageal cancer,however,are mainly unknown.AIM To identify cuprotosis-related genes that are differentially expressed in esophageal cancer and investigate their prognostic significance.METHODS With|log fold change|>1 and false discovery rate<0.05 as criteria,the Wilcox test was used to evaluate the differentially expressed genes between 151 tumor tissues and 151 normal esophageal tissues.Cuproptosis-related genes were selected to be linked with prognosis using univariate Cox regression analysis.Genes were separated into high-and low-expression groups based on their cutoff value of gene expression,and the correlation between the two groups and overall survival or progression-free survival was investigated using the log-rank test.The C-index,calibration curve,and receiver operator characteristic(ROC)curve were used to assess a nomogram containing clinicopathological characteristics and cuproptosis-related genes.RESULTS Pyruvate dehydrogenase A1(PDHA1)was found to be highly correlated with prognosis in univariate Cox regression analysis(hazard ratio=22.96,95%confidence interval=3.09-170.73;P=0.002).According to Kaplan-Meier survival curves,low expression of PDHA1 was associated with a better prognosis(log-rank P=0.0007).There was no significant correlation between PDHA1 expression and 22 different types of immune cells.Tumor necrosis factor superfamily member 15(TNFSF15)(P=3.2×10^(-6);r=0.37),TNFRSF14(P=8.1×10^(-8);r=0.42),H long terminal repeat-associating 2(P=6.0×10^(-8);r=0.42)and galectin 9(P=3.1×10^(-6);r=0.37)were all found to be considerably greater in the high PDHA1 expression group,according to an analysis of genes related to 47 immunological checkpoints.The low PDHA1 expression group had significantly lower levels of cluster of differentiation 44(CD44)(P=0.00028;R=-0.29),TNFRSF18(P=1.2×10^(-5);R=-0.35),programmed cell death 1 ligand 2(P=0.0032;R=-0.24),CD86(P=0.018;R=-0.19),and CD40(P=0.0047;R=-0.23),and the differences were statistically significant.We constructed a prognostic nomogram incorporating pathological type,tumor-node-metastasis stage,and PDHA1 expression,and the C-index,calibration curve,and ROC curve revealed that the nomogram’s predictive performance was good.CONCLUSION Cuproptosis-related genes can be used as a prognostic predictor for esophageal cancer patients,providing novel insights into cancer treatment.
