Integrative Analysis Identifies NSUN2 as an Essential Coordinator for Glioma Malignancy and Glucose Metabolism

ABSTRACT Background Glioma, particularly glioblastoma, is the most common and aggressive primary brain tumor, with poor prognosis due to its metabolic heterogeneity. NSUN2, an m5C RNA methyltransferase and direct glucose sensor, has been implicated in various malignancies, but its role in glioma remains unclear. Methods Bioinformatic analysis was performed on multiple public databases and our glioma dataset from West China Hospital (WCH). In vitro experiments were conducted to assess the effects of NSUN2 knockdown on glioma cell proliferation, migration, and chemotherapeutic sensitivity. Transcriptomic analysis was employed to obtain mechanistic insights. Results NSUN2 expression was significantly upregulated in gliomas and correlated with higher tumor grade and poor prognosis. NSUN2 knockdown reduced glioma cell proliferation, migration, and increased sensitivity to temozolomide. Transcriptomic analysis revealed that NSUN2 knockdown downregulated key genes involved in glioma progression. Mechanistically, NSUN2 positively regulates the activity of mTORC1 signaling, as indicated by phosphorylated S6 ribosomal protein and 4EBP1. Moreover, NSUN2 overexpression reciprocally increased tumor volume compared with controls, indicating NSUN2 promoting glioma cell proliferation in vivo. Conclusions Our findings highlight NSUN2 as a critical regulator of glioma malignancy. Targeting NSUN2 disrupts key pathways in glioma progression, suggesting it as a promising therapeutic target. Our work underscores the potential of NSUN2 inhibition to enhance treatment efficacy and improve patient outcomes in glioma.