Gliomas are malignant tumors in the central nervous system. Cuproptosis is a newly discovered cell death mechanism targeting lipoylated tricarboxylic acid cycle proteins. Previous studies have found that cuproptosis participates in tumor progression, but its role in gliomas is still elusive. Here, we systematically explored the bulk-tumor and single-cell transcriptome data to reveal its role in gliomas. The cuproptosis activity score (CuAS) was constructed based on cuproptosis-related genes, and machine learning techniques validated the score stability. High CuAS gliomas were more likely to have a poor prognosis and an aggressive mesenchymal (MES) subtype. Subsequently, the SCENIC algorithm predicted 20 CuAS-related transcription factors (TFs) in gliomas. Function enrichment and microenvironment analyses found that CuAS was associated with tumor immune infiltration. Accordingly, intercellular communications between neoplasm and immunity were explored by the R package "Cellchat". Five signaling pathways and 8 ligand-receptor pairs including ICAM1, ITGAX, ITGB2, ANXA1-FRR1, and the like, were identified to suggest how cuproptosis activity connected neoplastic and immune cells. Critically, 13 potential drugs targeting high CuAs gliomas were predicted according to the CTRP and PRISM databases, including oligomycin A, dihydroartemisinin, and others. Taken together, cuproptosis is involved in glioma aggressiveness, neoplasm-immune interactions, and may be used to assist in drug selection.

Objectives: Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression.Materials and Methods: Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single‐cell RNA‐Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony‐forming assay and flow cytometry.Results: The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high‐risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high‐risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase.Conclusions: Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan‐cancer.

Introduction: Pentraxin 3 (PTX3) is an essential regulator of the immune system. However, the immune‐modulatory role of PTX3 in the tumor microenvironment of glioma has not been elucidated.Methods: The RNA seq samples were obtained from The Cancer Genome Atlas (TCGA) and the China Glioma Genome Atlas (CGGA) datasets. The single‐cell sequencing data of glioblastoma (GBM) samples were obtained from the Single Cell Portal platform (http://singlecell.broadinstitute.org). Immunohistochemistry was used to assess PTX3 expression, HAVCR2, PD‐1, PD‐L1, and CD276 in glioma sections from the Xiangya cohort (n = 60). Multiplex immunofluorescence staining of PTX3, CD68, and CD163 was performed in several solid cancer types, including GBM. HMC3 was cocultured with U251 and U87, and transwell assay and flow cytometry assay were performed to explore the migration and polarization activity of HMC3.Results: PTX3 expression is significantly increased in GBM. PTX3 expression predicts worse survival in the Xiangya cohort. PTX3 is closely related to the expression of PD‐1, PD‐L1, CD276, and HAVCR2 in the tumor microenvironment. Additionally, PTX3 is involved in tumorigenic and immunogenic processes, especially the activity of macrophages based on various signaling pathways in cellular communications and critical transcription factors. Specifically, PTX3 actively mediates macrophages' infiltration, migration, and inflammation‐resolving‐polarization. PTX3 could also predict immunotherapy response.Conclusion: PTX3 is critically involved in macrophage infiltration, migration, and inflammation‐resolving‐polarization and modulates an immunosuppressive microenvironment.

Gliomas are the most common and lethal primary malignant tumor of the brain. Routine treatment including surgical resection, chemotherapy, and radiotherapy produced limited therapeutic effect, while immunotherapy targeting the glioma microenvironment has offered a novel therapeutic option. PDIA5 protein is the member of PDI family, which is highly expressed in glioma and participates in glioma progression. Based on large-scale bioinformatics analysis, we discovered that PDIA5 expression level is upregulated in aggressive gliomas, with high PDIA5 expression predicting poor clinical outcomes. We also observed positive correlation between PDIA5 and immune infiltrating cells, immune related pathways, inflammatory activities, and other immune checkpoint members. Patients with high PDIA5 high-expression benefited from immunotherapies. Additionally, immunohistochemistry revealed that PDIA5 and macrophage biomarker CD68 were upregulated in high-grade gliomas, and patients with low PDIA5 level experienced favorable outcomes among 33 glioma patients. Single cell RNA sequencing exhibited that PDIA5 was in high level presenting in neoplastic cells and macrophages. Cell transfection and co-culture of glioma cells and macrophages revealed that PDIA5 in tumor cells mediated macrophages exhausting. Altogether, our findings indicate that PDIA5 overexpression is associated with immune infiltration in gliomas, and may be a promising therapeutic target for glioma immunotherapy.

Mitochondrial dysfunction and necroptosis are closely associated, and play vital roles in the medical strategy of multiple cardiovascular diseases. However, their implications in intracranial aneurysms (IAs) remain unclear. In this study, we aimed to explore whether mitochondrial dysfunction and necroptosis could be identified as valuable starting points for predictive, preventive, and personalized medicine for IAs. The transcriptional profiles of 75 IAs and 37 control samples were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), weighted gene co-expression network analysis, and least absolute shrinkage and selection operator (LASSO) regression were used to screen key genes. The ssGSEA algorithm was performed to establish phenotype scores. The correlation between mitochondrial dysfunction and necroptosis was evaluated using functional enrichment crossover, phenotype score correlation, immune infiltration, and interaction network construction. The IA diagnostic values of key genes were identified using machine learning. Finally, we performed the single-cell sequencing (scRNA-seq) analysis to explore mitochondrial dysfunction and necroptosis at the cellular level. In total, 42 IA-mitochondrial DEGs and 15 IA-necroptosis DEGs were identified. Screening revealed seven key genes invovled in mitochondrial dysfunction (KMO, HADH, BAX, AADAT, SDSL, PYCR1, and MAOA) and five genes involved in necroptosis (IL1B, CAMK2G, STAT1, NLRP3, and BAX). Machine learning confirmed the high diagnostic value of these key genes for IA. The IA samples showed higher expression of mitochondrial dysfunction and necroptosis. Mitochondrial dysfunction and necroptosis exhibited a close association. Furthermore, scRNA-seq indicated that mitochondrial dysfunction and necroptosis were preferentially up-regulated in monocytes/macrophages and vascular smooth muscle cells (VSMCs) within IA lesions. In conclusion, mitochondria-induced necroptosis was involved in IA formation, and was mainly up-regulated in monocytes/macrophages and VSMCs within IA lesions. Mitochondria-induced necroptosis may be a novel potential target for diagnosis, prevention, and treatment of IA.