SLC16A13 Promotes Malignant Progression in Glioma via Metabolic Reprogramming and Disruption of Monocarboxylate Homeostasis

Gliomas are the most prevalent primary malignant brain tumors with limited therapeutic targets. Aerobic glycolysis, a hallmark of glioma, depends on the SLC16 monocarboxylate transporter family, including established oncogenic members MCT1 and MCT4. SLC16A13, linked to systemic glucose homeostasis and cellular stress adaptation, remains uncharacterized in glioma. Given the critical role of metabolic flexibility in glioma pathophysiology, we hypothesized that SLC16A13 may represent a contributor to glioma metabolic reprogramming and malignant progression. This study systematically investigated SLC16A13 expression and clinical relevance using The Cancer Genome Atlas (TCGA) and a West China Hospital glioma cohort. Stable SLC16A13-knockdown models were established in U251 and U373 cells via lentiviral shRNA delivery. Cell proliferation, colony formation, apoptosis, and migration were assessed by CCK−8, colony formation, flow cytometry, and wound healing assays, respectively. A subcutaneous xenograft model was employed to evaluate tumor growth in vivo. Intracellular and extracellular metabolite concentrations were quantified by ELISA and HPLC. SLC16A13 was significantly upregulated in glioma tissues compared with non-tumor controls, and high expression was tightly correlated with advanced WHO grade, IDH wild-type status, TERT promoter mutation, and shorter overall survival (HR = 1.57, 95% CI: 1.08–2.27) and progression-free survival (HR = 1.66, 95% CI: 1.15–2.41). In vitro, SLC16A13 knockdown in U251 and U373 glioma cells suppressed proliferation, colony formation, and migration while concomitantly promoting apoptosis. In vivo, SLC16A13 silencing significantly attenuated xenograft tumor growth and reduced Ki−67 proliferative index. Mechanistically, SLC16A13 depletion caused intracellular accumulation of lactate (~ 1.9-fold), pyruvate (~ 2.3-fold), and ketone bodies, accompanied by a 32% increase in the lactate-to-pyruvate ratio and a 28% decrease in the β-hydroxybutyrate-to-acetoacetate ratio, changes consistent with altered monocarboxylate handling and perturbed cellular redox balance. These findings establish SLC16A13 as a previously unrecognized promoter of glioma malignant progression and an independent prognostic biomarker. By disrupting metabolic homeostasis, SLC16A13 contributes to tumor maintenance and aggressive behavior, highlighting its potential as a therapeutic target.