Abstract
Background/Objectives: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal therapy. Metabolic reprogramming, particularly increased dependence on glutamine, supports GBM bioenergetic, biosynthetic, and redox demands. This study aimed to systematically identify glutamine-associated metabolic regulators with prognostic relevance and biological plausibility in GBM. Methods: Transcriptomic data from TCGA and GTEx were analyzed using GEPIA2, with survival validation performed using the CGGA. Functional pathway enrichment, protein expression assessment, protein-protein interaction network analysis, tumor microenvironment evaluation, epigenetic profiling, and single-cell RNA sequencing validation were integrated to contextualize candidate genes. Pharmacogenomic correlation analysis and structure-based molecular docking were applied as supportive validation layers. Results: Ceruloplasmin (CP), Solute Carrier Family 25 Member 13 (SLC25A13), and Solute Carrier Family 38 Member 2 (SLC38A2) were selectively dysregulated and associated with poor clinical outcomes in GBM. CP was linked to redox regulation and stress-adaptive survival programs, SLC25A13 to mitochondrial metabolite exchange and glutamine-coupled nucleotide biosynthesis, and SLC38A2 to glutamine uptake, nutrient sensing, and mTORC1-MYC-associated growth signaling. Conclusions:CP, SLC25A13, and SLC38A2 emerge as clinically relevant glutamine-associated metabolic regulators in GBM, linking redox regulation, mitochondrial metabolite exchange, and glutamine-driven growth signaling. These findings highlight transport- and exchange-centered metabolic nodes as potential biomarkers and candidates for future metabolic targeting in GBM.