ASIC1-SOX8 axis in lower-grade glioma predicts good prognosis and is associated with inflammatory infiltration and...

Lower-grade glioma (LGG) is a molecularly heterogeneous tumor in which acidic microenvironments and immune interactions critically influence prognosis. Acid-sensing ion channels (ASICs), particularly ASIC1, remain understudied in glioma biology despite their pH-sensing roles. This study investigates ASIC1/ASIC4 in LGG prognosis, immune regulation, and molecular subtyping.

Multi-omics analyses integrated TCGA and CGGA datasets (n = 696 LGG) with bioinformatics tools (TIMER, GEPIA, TISIDB). ASIC expression, immune infiltration, and checkpoint molecules were evaluated. Prognostic significance was assessed via Kaplan-Meier, Cox regression, and PrognoScan. Mechanistic links to SOX8 were validated through correlation analyses, functional enrichment, and immunohistochemistry (n = 78 LGG).

ASIC1/ASIC4 were upregulated in LGG versus normal tissues and inversely correlated with immune infiltration (B cells, CD8⁺/CD4⁺ T cells; P < 0.05). High ASIC1 expression predicted improved survival (HR = 0.38, P = 2.2 × 10^-7), independent of age/tumor grade, and showed negative associations with immune checkpoints (PDCD1, CD274; P < 0.01). ASIC1-SOX8 co-expression (Pearson r = 0.73) was enriched in IDH-mutant 1p/19q co-deleted subtypes and grade II tumors. Immunohistochemistry confirmed higher ASIC1/SOX8 protein levels in grade II versus III gliomas (P < 0.05). Functional analyses linked ASIC1 to suppressed inflammatory pathways (IL2-STAT5, complement cascades).

The ASIC1-SOX8 axis emerges as a dual prognostic biomarker and molecular subtype regulator in LGG, linking acidic microenvironments to immune evasion and IDH-driven glioma classification. Its clinical relevance in stratifying low-grade, IDH-mutant tumors highlights therapeutic potential for microenvironment-targeted immunotherapy.