MFSD2A as a prognostic biomarker in low-grade glioma: mechanistic links to immune suppression

• MFSD2A overexpression predicts poor survival in LGG. • Promoter hypomethylation correlates with higher MFSD2A expression. • MFSD2A is associated with immune infiltration, angiogenesis, and BBB integrity. • MFSD2A is a potential prognostic biomarker and therapeutic target for LGG. This study investigates the role of major facilitator superfamily domain containing 2A (MFSD2A) in low-grade glioma (LGG) progression, focusing on its association with tumor immune infiltration and patient survival. Using GTEx (normal tissues) and TCGA (LGG) datasets, we observed elevated MFSD2A mRNA levels in LGG versus normal brain tissue. Kaplan-Meier and multivariate Cox analyses revealed that low MFSD2A expression correlated with improved overall survival (OS) and disease-specific survival (DSS), independent of clinicopathological factors (WHO grade, IDH status, 1p/19q codeletion, etc.). DNA methylation analysis further supported its prognostic value. Gene enrichment (GSEA) showed high MFSD2A expression enriched in immune/cytokine pathways, while low expression linked to neural signaling. Network analyses of protein interactomes identified MFSD2A as a key node exhibiting inverse associations with certain lymphoid subpopulations. Correlation analyses revealed that MFSD2A expression was positively associated with blood–brain barrier integrity, angiogenesis, and select immune checkpoint pathways. This transporter protein demonstrated significant enrichment in pathways characteristic of the tumor stromal niche. These results establish MFSD2A as an immunological determinant in LGG pathogenesis, providing mechanistic insights into its prognostic and therapeutic relevance.