Evaluation of Significance of SERPINA3 and SPP1 in Driving Glioma Progression: Suggestive of Dysregulation in Brain Inflammatory Pathway and Tumour Remodelling

Glioma is a highly aggressive malignancy with poor prognosis, particularly in grade IV glioblastoma, and monitoring disease progression is challenging due to tumour heterogeneity and limited biomarkers. We investigated SERPINA3 and SPP1 as dual biomarkers reflecting the tumour microenvironment and glioma progression. In silico analyses revealed cell-type specificity, with SERPINA3 enriched in astrocytes and SPP1 in microglia/macrophages, supported by lineage marker correlations. Pan-cancer analysis showed highest expression in glioma, while Alzheimer’s disease datasets indicated lower dysregulation. Co-expression and pathway analyses linked these genes to immunoregulatory processes, extracellular matrix remodelling, and stress responses. Multi-omic integration suggested regulation through transcription factors, epigenetic modifications, and miRNA-mediated mechanisms. Immune infiltration analysis revealed a shift from cytotoxic to macrophage-dominant, immunosuppressive microenvironments during progression from low-grade glioma to glioblastoma. High SERPINA3 and SPP1 expression was prognostic in low-grade glioma, and ROC analysis demonstrated excellent performance in distinguishing glioblastoma from lower-grade tumours. Independent validation in the Chinese Glioma Genome Atlas cohort confirmed these findings. Collectively, SERPINA3 and SPP1 serve as robust biomarkers of glioma progression and immune microenvironment remodelling, with potential for disease stratification and therapeutic targeting.