Objective To explore the expression characteristics， clinical correlations， and potential biological functions of the ATPase Na+/K+ transporting subunit alpha 2（ ATP1A2） gene in glioma， and thoroughly analyze its biological role in the pathological progression of glioma. Methods mRNA sequencing data from the Chinese Glioma Genome Atlas（ CGGA）（ n=325） and The Cancer Genome Atlas（ TCGA）（ n=675） glioma cohorts were retrospectively analyzed to assess ATP1A2 expression levels. Based on the X-tile platform and the surv_ cutpoint function in the R language's survminer package， the cutoff value most significantly associated with survival was selected（ CGGA： 6.446 1， TCGA： 12.660 23）. The group with ATP1A2 expression levels above the most significant cutoff value was classified as the ATP1A2 high-expression group， while the group with levels below the cutoff was classified as the ATP1A2 low-expression group. Kaplan-Meier curve， log-rank test， and Cox proportional hazard model were employed to evaluate the relationship between ATP1A2 expression and overall survival in patients. The functions of genes co-expressed with ATP1A2 were explored through Gene Ontology（ GO） annotation and Kyoto Encyclopedia of Genes and Genomes（ KEGG） pathway enrichment analysis. Results The comparison of clinical and pathological characteristics between CGGA and TCGA cohorts revealed statistically significant differences between the two cohorts in primary WHO grading， isocitrate dehydrogenase（ IDH） mutation status， and 1p/19q co-deletion（ all P ＜ 0.05）. mRNA sequencing data from two cohorts showed statistically significant differences in ATP1A2 expression levels in WHO grade 2 to 4 glioma tissues（ F=28.67， 48.26； both P ＜ 0.01）， with a decreasing trend observed as tumor grade increased. Further analysis revealed that in both the CGGA and TCGA databases， ATP1A2 expression was statistically higher in IDH-mutant gliomas compared to IDH wild-type gliomas（ both P ＜ 0.01）. No statistical differences in ATP1A2 expression were observed across different O6-methylguanine-DNA methyltransferase（ MGMT） promoter methylation states（ all P＞ 0.05）. Analysis of CGGA and GSE131928 single-cell data indicated that ATP1A2 was primarily expressed in tumor cells. Patients with low ATP1A2 expression exhibited significantly short overall survival in both the CGGA and TCGA cohorts， with statistically significant differences（ CGGA： ATP1A2 high-expression group 6.411 years， ATP1A2 low-expression group 1.203 years， χ2=41.05， P＜0.01； TCGA： ATP1A2 high-expression group 4.233 years， ATP1A2 low-expression group 1.467 years， χ2=28.81， P＜0.01）. Univariate［ HR=0.721， 95%CI（ 0.654， 0.794）］ and multivariate Cox［ HR=0.793， 95%CI（ 0.716， 0.879）］ analysis demonstrated that ATP1A2 expression was an independent risk factor for glioma， with statistically significant differences （P ＜ 0.01）. GO enrichment analysis revealed that genes positively correlated with ATP1A2 in the TCGA and CGGA databases were primarily involved in biological processes such as acidic amino acid transport， L-glutamate transmembrane transport， and amino acid transport. KEGG pathway enrichment analysis indicated that genes positively correlated with ATP1A2 in the CGGA database were associated with GABAergic synapses and neuroactive ligand signaling. Genes positively correlated with ATP1A2 in the TCGA database were associated with the metabolism of alanine， aspartate， and glutamate， as well as the reabsorption of bicarbonate in the proximal tubule. Conclusions This study confirms that ATP1A2 is an independent prognostic biomarker for glioma， with its low expression indicating poor patient prognosis. This discovery not only provides a novel molecular tool for assessing the prognosis of gliomas， but also identifies potential targets within associated biological pathways for developing new therapeutic strategies targeting ion metabolism and neurotransmitter homeostasis within the tumor microenvironment.