Sphingolipid metabolic enzyme GLA expression in gliomas: prognostic implications and therapeutic potential.

BACKGROUND: Gliomas are the most common primary brain tumors and show marked molecular heterogeneity and variable clinical outcomes, highlighting the need for reliable prognostic biomarkers. METHODS: We analyzed TCGA and CGGA datasets to identify prognosis-related genes in glioma and performed single-cell analysis and functional validation in glioma cell lines. RESULTS: Ten prognosis-related genes were identified, among which GLA showed the strongest association with survival. Elevated GLA expression was significantly associated with higher WHO grade, therapy resistance, and worse prognosis. Time-dependent ROC analysis showed favorable predictive performance for 1-, 3-, and 5-year survival. Single-cell RNA sequencing revealed preferential GLA expression in tumor-associated astrocytes and grade-dependent upregulation. GLA expression was associated with sphingolipid metabolism, hypoxia-related pathways, and ERAD-related pathways, including EDEM2 expression. In glioma cell lines, GLA knockdown suppressed cell viability and downregulated EDEM2. Cross-database analyses further supported the diagnostic and prognostic relevance of GLA across cohorts. CONCLUSION: GLA may serve as a prognostic biomarker in glioma and is associated with metabolic and ERAD-related alterations, providing a potential direction for further mechanistic and therapeutic investigation.