Copper homeostasis and cuproptosis in cancer immunity and therapy.

Copper is an essential nutrient for maintaining enzyme activity and transcription factor function. Excess copper results in the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), which correlates to the mitochondrial tricarboxylic acid (TCA) cycle, resulting in proteotoxic stress and eliciting a novel cell death modality: cuproptosis. Cuproptosis exerts an indispensable role in cancer progression, which is considered a promising strategy for cancer therapy. Cancer immunotherapy has gained extensive attention owing to breakthroughs in immune checkpoint blockade; furthermore, cuproptosis is strongly connected to the modulation of antitumor immunity. Thus, a thorough recognition concerning the mechanisms involved in the modulation of copper metabolism and cuproptosis may facilitate improvement in cancer management. This review outlines the cellular and molecular mechanisms and characteristics of cuproptosis and the links of the novel regulated cell death modality with human cancers. We also review the current knowledge on the complex effects of cuproptosis on antitumor immunity and immune response. Furthermore, potential agents that elicit cuproptosis pathways are summarized. Lastly, we discuss the influence of cuproptosis induction on the tumor microenvironment as well as the challenges of adding cuproptosis regulators to therapeutic strategies beyond traditional therapy.

The cuproptosis-related signature predicts the prognosis and immune microenvironments of primary diffuse gliomas: a comprehensive analysis.

BACKGROUND: Evidence has revealed a connection between cuproptosis and the inhibition of tumor angiogenesis. While the efficacy of a model based on cuproptosis-related genes (CRGs) in predicting the prognosis of peripheral organ tumors has been demonstrated, the impact of CRGs on the prognosis and the immunological landscape of gliomas remains unexplored. METHODS: We screened CRGs to construct a novel scoring tool and developed a prognostic model for gliomas within the various cohorts. Afterward, a comprehensive exploration of the relationship between the CRG risk signature and the immunological landscape of gliomas was undertaken from multiple perspectives. RESULTS: Five genes (NLRP3, ATP7B, SLC31A1, FDX1, and GCSH) were identified to build a CRG scoring system. The nomogram, based on CRG risk and other signatures, demonstrated a superior predictive performance (AUC of 0.89, 0.92, and 0.93 at 1, 2, and 3 years, respectively) in the training cohort. Furthermore, the CRG score was closely associated with various aspects of the immune landscape in gliomas, including immune cell infiltration, tumor mutations, tumor immune dysfunction and exclusion, immune checkpoints, cytotoxic T lymphocyte and immune exhaustion-related markers, as well as cancer signaling pathway biomarkers and cytokines. CONCLUSION: The CRG risk signature may serve as a robust biomarker for predicting the prognosis and the potential viability of immunotherapy responses. Moreover, the key candidate CRGs might be promising targets to explore the underlying biological background and novel therapeutic interventions in gliomas.

Cuproptosis: A novel therapeutic target for overcoming cancer drug resistance.

Cuproptosis is a newly identified form of cell death driven by copper. Recently, the role of copper and copper triggered cell death in the pathogenesis of cancers have attracted attentions. Cuproptosis has garnered enormous interest in cancer research communities because of its great potential for cancer therapy. Copper-based treatment exerts an inhibiting role in tumor growth and may open the door for the treatment of chemotherapy-insensitive tumors. In this review, we provide a critical analysis on copper homeostasis and the role of copper dysregulation in the development and progression of cancers. Then the core molecular mechanisms of cuproptosis and its role in cancer is discussed, followed by summarizing the current understanding of copper-based agents (copper chelators, copper ionophores, and copper complexes-based dynamic therapy) for cancer treatment. Additionally, we summarize the emerging data on copper complexes-based agents and copper ionophores to subdue tumor chemotherapy resistance in different types of cancers. We also review the small-molecule compounds and nanoparticles (NPs) that may kill cancer cells by inducing cuproptosis, which will shed new light on the development of anticancer drugs through inducing cuproptosis in the future. Finally, the important concepts and pressing questions of cuproptosis in future research that should be focused on were discussed. This review article suggests that targeting cuproptosis could be a novel antitumor therapy and treatment strategy to overcome cancer drug resistance.

The Convergence of Sonodynamic Therapy and Cuproptosis in the Dual-Responsive Biomimetic CytoNano for Precision Mitochondrial Intervention in Cancer Treatment.

The integration of sonodynamic therapy (SDT) with cuproptosis for targeted cancer treatment epitomizes a significant advancement in oncology. Herein, we present a dual-responsive therapeutic system, "CytoNano", which combines a cationic liposome infused with copper-nitride nanoparticles and oxygen-rich perfluorocarbon (Lip@Cu3N/PFC-O2), all enveloped in a biomimetic coating of neutrophil membrane and acid-responsive carboxymethylcellulose. CytoNano leverages the cellular mimicry of neutrophils and acid-responsive materials, enabling precise targeting of tumors and their acidic microenvironment. This strategic design facilitates the targeted release of Lip@Cu3N/PFC-O2 within the tumor, enhancing cancer cell uptake and mitochondrial localization. Consequently, it amplifies the therapeutic efficacy of both Cu3N-driven SDT and cuproptosis while preserving healthy tissues. Additionally, CytoNano's ultrasound responsiveness enhances intratumoral oxygenation, overcoming physiological barriers and initiating a combined sonodynamic-cuproptotic effect that induces multiple cell death pathways. Thus, we pioneer a biomimetic approach in precise sonodynamic cuproptosis, revolutionizing cancer therapy.

Cuproptosis: Mechanism, role, and advances in urological malignancies.

Prostate, bladder, and kidney cancers are the most common malignancies of the urinary system. Chemotherapeutic drugs are generally used as adjuvant treatment in the middle, late, or recurrence stages after surgery for urologic cancers. However, traditional chemotherapy is plagued by problems such as poor efficacy, severe side effects, and complications. Copper-containing nanomedicines are promising novel cancer treatment modalities that can potentially overcome these disadvantages. Copper homeostasis and cuproptosis play crucial roles in the development, adaptability, and therapeutic sensitivity of urological malignancies. Cuproptosis refers to the direct binding of copper ions to lipoylated components of the tricarboxylic acid cycle, leading to protein oligomerization, loss of iron-sulfur proteins, proteotoxic stress, and cell death. This review focuses on copper homeostasis and cuproptosis as well as recent findings on copper and cuproptosis in urological malignancies. Furthermore, we highlight the potential therapeutic applications of copper- and cuproptosis-targeted therapies to better understand cuproptosis-based drugs for the treatment of urological tumors in the future.

Cuproptosis associated cytoskeletal destruction contributes to podocyte injury in chronic kidney disease.

The podocyte cytoskeleton determines the stability of podocyte structure and function, and their imbalance plays a pathogenic role in podocyte diseases. However, the underlying mechanism of podocyte cytoskeleton damage is not fully understood. Here, we investigate the specific role of cuproptosis in inducing podocyte cytoskeleton injury. In vitro and in vivo studies, exposure to high levels of copper and adriamycin (ADR) caused significant increases in copper concentration in intracellular and renal tissue. Moreover, excessive accumulation of copper induced cuproptosis, resulting in the destruction of the podocyte cytoskeleton. However, inhibition of copper accumulation to reduce cuproptosis also significantly alleviated the damage of podocyte cytoskeleton. In addition, inhibition of cuproptosis mitigated ADR-induced mitochondrial damage as well as the production of reactive oxygen species and depolarization of mitochondrial membrane potential, and restored ATP synthesis. Among the transcriptome sequencing data, the difference of CXCL5 was the most significant. Both high copper and ADR exposure can cause up-regulation of CXCL5, and CXCL5 deletion inhibits the occurrence of cuproptosis, thereby alleviating the podocyte cytoskeleton damage. This suggests that CXCL5 may act upstream of cuproptosis that mediates podocyte cytoskeleton damage. In conclusion, cuproptosis induced by excessive copper accumulation may induce podocyte cytoskeleton damage by promoting mitochondrial dysfunction, thereby causing podocyte injury. This indicates that cuproptosis plays an important role in the pathogenesis of podocyte injury and provides a basis for seeking potential targets for the treatment of chronic kidney disease.

Deciphering the role of cuproptosis-related lncRNAs in shaping the lung cancer immune microenvironment: A comprehensive prognostic model.

Cuproptosis plays an important role in cancer, but its role in lung cancer remains unknown. Transcriptional profiles, clinical details and mutation data were acquired from the Cancer Genome Atlas database through a variety of methods. The analysis of this publicly available data was comprehensively performed using R software along with its relevant packages, ensuring a thorough examination of the information. In this study, we conducted a detailed analysis of cuproptosis-related genes and lncRNA co-expression, identifying 129 relevant lncRNAs and establishing a prognostic model with four key lncRNAs (LINC00996, RPARP-AS1, SND1-IT1, TMPO-AS1). Utilizing data from TCGA and GEO databases, the model effectively categorized patients into high- and low-risk groups, showing significant survival differences. Correlation analysis highlighted specific relationships between individual lncRNAs and cuproptosis genes. Our survival analysis indicated a higher survival rate in the low-risk group across various cohorts. Additionally, the model's predictive accuracy was confirmed through independent prognostic analysis and ROC curve evaluations. Functional enrichment analysis revealed distinct biological pathways and immune functions between risk groups. Tumour mutation load analysis differentiated high- and low-risk groups by their mutation profiles. Drug sensitivity analysis and immune infiltration studies using the CIBERSORT algorithm further elucidated the potential treatment responses in different risk groups. This comprehensive evaluation underscores the significance of lncRNAs in cuproptosis and their potential as biomarkers for lung cancer prognosis and immune microenvironment.

METTL3 as a novel diagnosis and treatment biomarker and its association with glycolysis, cuproptosis and ceRNA in oesophageal carcinoma.

METTL3 has been shown to be involved in regulating a variety of biological processes. However, the relationship between METTL3 expression and glycolysis, cuproptosis-related genes and the ceRNA network in oesophageal carcinoma (ESCA) remains unclear. ESCA expression profiles from databases were obtained, and target genes were identified using differential analysis and visualization. Immunohistochemistry (IHC) staining assessed METTL3 expression differences. Functional enrichment analysis using GO, KEGG and GSEA was conducted on the co-expression profile of METTL3. Cell experiments were performed to assess the effect of METTL3 interference on tumour cells. Correlation and differential analyses were carried out to assess the relationship between METTL3 with glycolysis and cuproptosis. qRT-PCR was used to validate the effects of METTL3 interference on glycolysis-related genes. Online tools were utilized to screen and construct ceRNA networks based on the ceRNA theory. METTL3 expression was significantly higher in ESCA compared to the controls. The IHC results were consistent with the above results. Enrichment analysis revealed that METTL3 is involved in multiple pathways associated with tumour development. Significant correlations were observed between METTL3 and glycolysis-related genes and cuproptosis-related gene. Experiments confirmed that interfered with METTL3 significantly inhibited glucose uptake and lactate production in tumour cells, and affected the expression of glycolytic-related genes. Finally, two potential ceRNA networks were successfully predicted and constructed. Our study establishes the association between METTL3 overexpression and ESCA progression. Additionally, we propose potential links between METTL3 and glycolysis, cuproptosis and ceRNA, presenting a novel targeted therapy strategy for ESCA.

Immune patterns of cuproptosis in ischemic heart failure: A transcriptome analysis.

Cuproptosis is a recently discovered programmed cell death pattern that affects the tricarboxylic acid (TCA) cycle by disrupting the lipoylation of pyruvate dehydrogenase (PDH) complex components. However, the role of cuproptosis in the progression of ischemic heart failure (IHF) has not been investigated. In this study, we investigated the expression of 10 cuproptosis-related genes in samples from both healthy individuals and those with IHF. Utilizing these differential gene expressions, we developed a risk prediction model that effectively distinguished healthy and IHF samples. Furthermore, we conducted a comprehensive evaluation of the association between cuproptosis and the immune microenvironment in IHF, encompassing infiltrated immunocytes, immune reaction gene-sets and human leukocyte antigen (HLA) genes. Moreover, we identified two different cuproptosis-mediated expression patterns in IHF and explored the immune characteristics associated with each pattern. In conclusion, this study elucidates the significant influence of cuproptosis on the immune microenvironment in ischemic heart failure (IHF), providing valuable insights for future mechanistic research exploring the association between cuproptosis and IHF.

Identification and validation of cuproptosis-related molecular clusters in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease worldwide. Cuproptosis has recently been reported as a form of cell death that appears to drive the progression of a variety of diseases. This study aimed to explore cuproptosis-related molecular clusters and construct a prediction model. The gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. The associations between molecular clusters of cuproptosis-related genes and immune cell infiltration were investigated using 50 NAFLD samples. Furthermore, cluster-specific differentially expressed genes were identified by the WGCNA algorithm. External datasets were used to verify and screen feature genes, and nomograms, calibration curves and decision curve analysis (DCA) were performed to verify the performance of the prediction model. Finally, a NAFLD-diet mouse model was constructed to further verify the predictive analysis, thus providing new insights into the prediction of NAFLD clusters and risks. The role of cuproptosis in the development of non-alcoholic fatty liver disease and immune cell infiltration was explored. Non-alcoholic fatty liver disease was divided into two cuproptosis-related molecular clusters by unsupervised clustering. Three characteristic genes (ENO3, SLC16A1 and LEPR) were selected by machine learning and external data set validation. In addition, the accuracy of the nomogram, calibration curve and decision curve analysis in predicting NAFLD clusters was also verified. Further animal and cell experiments confirmed the difference in their expression in the NAFLD mouse model and Mouse hepatocyte cell line. The present study explored the relationship between non-alcoholic fatty liver disease and cuproptosis, providing new ideas and targets for individual treatment of the disease.

FDX1 regulates cellular protein lipoylation through direct binding to LIAS.

Ferredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of ferredoxins as electron donors enables them to participate in many metabolic processes including steroid, heme, vitamin D, and Fe-S cluster biosynthesis in different organisms. However, the unique natural function(s) of each of the two human ferredoxins (FDX1 and FDX2) are still poorly characterized. We recently reported that FDX1 is both a crucial regulator of copper ionophore-induced cell death and serves as an upstream regulator of cellular protein lipoylation, a mitochondrial lipid-based post-translational modification naturally occurring on four mitochondrial enzymes that are crucial for TCA cycle function. Here we show that FDX1 directly regulates protein lipoylation by binding the lipoyl synthase (LIAS) enzyme promoting its functional binding to the lipoyl carrier protein GCSH and not through indirect regulation of cellular Fe-S cluster biosynthesis. Metabolite profiling revealed that the predominant cellular metabolic outcome of FDX1 loss of function is manifested through the regulation of the four lipoylation-dependent enzymes ultimately resulting in loss of cellular respiration and sensitivity to mild glucose starvation. Transcriptional profiling established that FDX1 loss-of-function results in the induction of both compensatory metabolism-related genes and the integrated stress response, consistent with our findings that FDX1 loss-of-function is conditionally lethal. Together, our findings establish that FDX1 directly engages with LIAS, promoting its role in cellular protein lipoylation, a process essential in maintaining cell viability under low glucose conditions.

Crosstalk between metabolism and cell death in tumorigenesis.

It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.

Cuproptosis in lung cancer: therapeutic options and prognostic models.

Lung cancer (LC) is a serious threat to mankind. The survival of LC patients is still poor despite the enormous efforts that have been made to develop novel treatments. A copper-dependent cell death termed cuproptosis is distinct from known programmed cell death (PCD). Cuproptosis is induced by the disruption of the binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins of mitochondrial respiratory chains. Potential approaches for treating LC are inducing cell cuproptosis and targeting cell copper death mechanisms. Thus, in this review, we summarize the systemic and cellular metabolic processes of copper. We highlight the possible therapeutic options of employing copper ionophores and chelators for inducing cuproptosis. Moreover, we summarize the prognostic models based on cuproptosis-related genes (CRGs) to identify promising biomarkers for tumor diagnosis and therapy. This review aims to provide a comprehensive summary of CRGs-based prognostic models and promising therapeutic options for cuproptosis induction in LC.

From ferroptosis to cuproptosis, and calcicoptosis, to find more novel metals-mediated distinct form of regulated cell death.

Regulated cell death (RCD), also known as programmed cell death (PCD), plays a critical role in various biological processes, such as tissue injury/repair, development, and homeostasis. Dysregulation of RCD pathways can lead to the development of many human diseases, such as cancer, neurodegenerative disorders, and cardiovascular diseases. Maintaining proper metal ion homeostasis is critical for human health. However, imbalances in metal levels within cells can result in cytotoxicity and cell death, leading to a variety of diseases and health problems. In recent years, new types of metal overload-induced cell death have been identified, including ferroptosis, cuproptosis, and calcicoptosis. This has prompted us to examine the three defined metal-dependent cell death types, and discuss other metals-induced ferroptosis, cuproptosis, and disrupted Ca2+ homeostasis, as well as the roles of Zn2+ in metals' homeostasis and related RCD. We have reviewed the connection between metals-induced RCD and various diseases, as well as the underlying mechanisms. We believe that further research in this area will lead to the discovery of novel types of metal-dependent RCD, a better understanding of the underlying mechanisms, and the development of new therapeutic strategies for human diseases.

Mechanisms of cuproptosis and its relevance to distinct diseases.

Copper is a trace element required by the organism, but once the level of copper exceeds the threshold, it becomes toxic and even causes death. The underlying mechanisms of copper-induced death are inconclusive, with different studies showing different opinions on the mechanism of copper-induced death. Multiple investigations have shown that copper induces oxidative stress, endoplasmic reticulum stress, nucleolar stress, and proteasome inhibition, all of which can result in cell death. The latest research elucidates a copper-dependent death and denominates it as cuproptosis. Cuproptosis takes place through the combination of copper and lipoylated proteins of the tricarboxylic acid cycle, triggering agglomeration of lipoylated proteins and loss of iron-sulfur cluster proteins, leading to proteotoxic stress and ultimately death. Given the toxicity and necessity of copper, abnormal levels of copper lead to diseases such as neurological diseases and cancer. The development of cancer has a high demand for copper, neurological diseases involve the change of copper contents and the binding of copper to proteins. There is a close relationship between these two kinds of diseases and copper. Here, we summarize the mechanisms of copper-related death, and the association between copper and diseases, to better figure out the influence of copper in cell death and diseases, thus advancing the clinical remedy of these diseases.

Cuproptosis and copper deficiency in ischemic vascular injury and repair.

Ischemic vascular diseases are on the rise globally, including ischemic heart diseases, ischemic cerebrovascular diseases, and ischemic peripheral arterial diseases, posing a significant threat to life. Copper is an essential element in various biological processes, copper deficiency can reduce blood vessel elasticity and increase platelet aggregation, thereby increasing the risk of ischemic vascular disease; however, excess copper ions can lead to cytotoxicity, trigger cell death, and ultimately result in vascular injury through several signaling pathways. Herein, we review the role of cuproptosis and copper deficiency implicated in ischemic injury and repair including myocardial, cerebral, and limb ischemia. We conclude with a perspective on the therapeutic opportunities and future challenges of copper biology in understanding the pathogenesis of ischemic vascular disease states.

Cuproptosis and Cu: a new paradigm in cellular death and their role in non-cancerous diseases.

Cuproptosis, a newly characterized form of regulated cell death driven by copper accumulation, has emerged as a significant mechanism underlying various non-cancerous diseases. This review delves into the complex interplay between copper metabolism and the pathogenesis of conditions such as Wilson's disease (WD), neurodegenerative disorders, and cardiovascular pathologies. We examine the molecular mechanisms by which copper dysregulation induces cuproptosis, highlighting the pivotal roles of key copper transporters and enzymes. Additionally, we evaluate the therapeutic potential of copper chelation strategies, which have shown promise in experimental models by mitigating copper-induced cellular damage and restoring physiological homeostasis. Through a comprehensive synthesis of recent advancements and current knowledge, this review underscores the necessity of further research to translate these findings into clinical applications. The ultimate goal is to harness the therapeutic potential of targeting cuproptosis, thereby improving disease management and patient outcomes in non-cancerous conditions associated with copper dysregulation.

Ferroptosis and cuproptposis in kidney Diseases: dysfunction of cell metabolism.

Metal ions play an important role in living organisms and are involved in essential physiological activities. However, the overload state of ions can cause excess free radicals, cell damage, and even cell death. Ferroptosis and cuproptosis are specific forms of cell death that are distinct from apoptosis, necroptosis, and other regulated cell death. These unique modalities of cell death, dependent on iron and copper, are regulated by multiple cellular metabolic pathways, including steady-state metal redox treatment mitochondrial activity of lipid, amino acid and glucose metabolism, and various signaling pathways associated with disease. Although the mechanisms of ferroptosis and cuproptosis are not yet fully understood, there is no doubt that ion overload plays a crucial act in these metal-dependent cell deaths. In this review, we discussed the core roles of ion overload in ferroptosis and cuproptosis, the association between metabolism imbalance and ferroptosis and cuproptosis, the extract the diseases caused by ion overload and current treatment modalities.

Integrative analysis of cuproptosis-associated genes for predicting immunotherapy response in single-cell and multi-cohort studies.

BACKGROUND: The role of genes associated with the cuproptosis cell signaling pathway in prognosis and immunotherapy in ovarian cancer (OC) has been extensively investigated. In this study, we aimed to explore these mechanisms and establish a prognostic model for patients with OC using bioinformatics techniques. METHODS: We obtained the single cell sequencing data of ovarian cancer from the Gene Expression Omnibus (GEO) database and preprocessed the data. We analyzed a variety of factors including cuproptosis cell signal score, transcription factors, tumorigenesis and progression signals, gene set variation analysis (GSVA) and intercellular communication. Differential gene analysis was performed between groups with high and low cuproptosis cell signal scores, as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Using bulk RNA sequencing data from The Cancer Genome Atlas, we used the least absolute shrinkage and selection operator (LASSO)-Cox algorithm to develop cuproptosis cell signaling pathword-related gene signatures and validated them with GEO ovarian cancer datasets. In addition, we analyzed the inherent rules of the genes involved in building the model using a variety of bioinformatics methods, including immune-related analyses and single nucleotide polymorphisms. Molecular docking is used to screen potential therapeutic drugs. To confirm the analysis results, we performed various wet experiments such as western blot, cell counting kit 8 (CCK8) and clonogenesis tests to verify the role of the Von Willebrand Factor (VWF) gene in two ovarian cancer cell lines. RESULTS: Based on single-cell data analysis, we found that endothelial cells and fibroblasts showed active substance synthesis and signaling pathway activation in OC, which further promoted immune cell suppression, cancer cell proliferation and metastasis. Ovarian cancer has a high tendency to metastasize, and cancer cells cooperate with other cells to promote disease progression. We developed a signature consisting of eight cuproptosis-related genes (CRGs) (MAGEF1, DNPH1, RARRES1, NBL1, IFI27, VWF, OLFML3 and IGFBP4) that predicted overall survival in patients with ovarian cancer. The validity of this model is verified in an external GEO validation set. We observed active infiltrating states of immune cells in both the high- and low-risk groups, although the specific cells, genes and pathways of activation differed. Gene mutation analysis revealed that TP53 is the most frequently mutated gene in ovarian cancer. We also predict small molecule drugs associated with CRGs and identify several potential candidates. VWF was identified as an oncogene in ovarian cancer, and the protein was expressed at significantly higher levels in tumor samples than in normal samples. The high-score model of the cuproptosis cell signaling pathway was associated with the sensitivity of OC patients to immunotherapy. CONCLUSIONS: Our study provides greater insight into the mechanisms of action of genes associated with the cuproptosis cell signaling pathway in ovarian cancer, highlighting potential targets for future therapeutic interventions.

Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis.

BACKGROUND: Currently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. METHODS: Original data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity. Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. RESULTS: Overall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C-C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. CONCLUSION: In the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.