Downregulation of SLC12A5 in glioblastoma multiforme: a novel prognostic biomarker associated with brain edema and radiomic features.

Glioblastoma multiforme (GBM), an aggressive brain tumor with a dismal prognosis, lacks robust prognostic biomarkers. In this study, we aimed to identify novel biomarkers using integrative bioinformatics, radiomics, and experimental validation. Using the GEO, TCGA, and CGGA datasets, we screened 387 differentially expressed genes (DEGs) and identified five hub genes (LOX, VEGFA, SERPINH1, SLC12A5, and VSNL1) linked to poor outcomes. Among these, SLC12A5 exhibited unique downregulation in GBM, in contrast to its upregulation in most other cancers. Functional analyses revealed that SLC12A5 suppressed the JAK-STAT3, E2F, and MYC pathways, whereas single-cell sequencing highlighted its predominant expression in astrocytes and microglia. Western blotting and immunohistochemistry validated that SLC12A5 downregulation correlated with increased brain edema volume (negative correlation, * p < 0.05) and activated MMP9/STAT3 signaling. Radiomics analysis demonstrated that SLC12A5 expression was associated with MRI features predictive of the IDH genotypes, offering non-invasive prognostic insights. Drug sensitivity screening identified six small molecules (PD0325901, ERK-6604, paclitaxel, ribociclib, TAF1, and lapatinib) that targeted SLC12A5-related pathways. Crucially, multivariate Cox regression analysis confirmed that SLC12A5 was an independent prognostic factor (HR p = 0.04). This study established SLC12A5 as a novel biomarker for GBM, uniquely bridging molecular dysregulation, edema pathogenesis, and radiomics with implications for prognosis and targeted therapy.