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NAGLU as a novel prognostic and functional biomarker in glioblastoma: integrated multi-Omics and experimental validation

bioinformatics
cell-biology
oncology
translational-medicine

Abstract

Purpose: This study aims to systematically investigate the expression pattern, clinical significance, and functional role of N -acetyl-α-glucosaminidase (NAGLU) in glioblastoma (GBM) through integrated bioinformatics analyses and experimental validation.
Patients and methods: Transcriptomic data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were analyzed to evaluate differential NAGLU expression between GBM and normal brain tissues. Co-expression analysis, protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, immune cell infiltration assessment using single-sample gene set enrichment analysis (ssGSEA), and correlation analysis with cuproptosis-related genes were performed. The diagnostic and prognostic value of NAGLU was assessed using receiver operating characteristic (ROC) analysis, Kaplan–Meier survival analysis, Cox regression, and nomogram modeling. In vitro validation was conducted using qRT-PCR, Western blotting, siRNA-mediated knockdown, and CCK-8 proliferation assays in U251 and LN229 glioblastoma cell lines.
Results: NAGLU expression is significantly upregulated in GBM tissues and glioblastoma cell lines compared with normal brain tissues and non-malignant glial cells. High NAGLU expression is significantly associated with unfavorable clinicopathological features and poor overall survival, serving as an independent prognostic factor in GBM. Functional enrichment analyses indicate that NAGLU-associated genes are mainly involved in lysosomal pathways, metabolic processes, and immune-related functions. NAGLU expression is significantly correlated with immune cell infiltration patterns and multiple cuproptosis-related metabolic genes. In vitro experiments demonstrate that siRNA-mediated knockdown of NAGLU markedly suppresses glioblastoma cell proliferation.
Conclusion: NAGLU is aberrantly overexpressed in glioblastoma and functions as an independent prognostic biomarker. Its association with lysosomal regulation, immune remodeling, metabolic stress responses, and tumor cell proliferation highlights NAGLU as a potential diagnostic indicator and therapeutic target in GBM.
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