Integrated multi-omics and machine learning identify OGDHL as a key regulator of glioblastoma progression and antitumor immunity via glutamine metabolism and histone lactylation.

BACKGROUND: Glioblastoma (GBM) has an extremely poor prognosis, and its malignant progression is closely associated with glutamine metabolic reprogramming and immune evasion; however, the key regulatory networks remain unclear.

METHODS: This study integrated bioinformatics data and identified key proteins through weighted gene co-expression network analysis (WGCNA), screening for differentially expressed proteins (DEPs), and machine learning algorithms. The functions and molecular mechanisms were validated using in vitro cell experiments and in vivo mouse models.

RESULTS: Oxoglutarate dehydrogenase L (OGDHL) was identified as the key protein in GBM. It was down-regulated in both GBM and low-grade glioma (LGG) tissues and was correlated with immune cell infiltration. OGDHL overexpression inhibited GBM cell proliferation and reduced glutamate, α-ketoglutarate (α-KG), lactate production, and programmed death-ligand 1 (PD-L1) expression, while promoting apoptosis. OGDHL overexpression enhanced CD8+ T cell-mediated cytotoxicity and interferon-γ (IFN-γ) secretion. Mechanistically, OGDHL overexpression suppressed histone H3 lysine 18 lactylation (H3K18la) enrichment, reduced luciferase activity, and inhibited PD-L1 expression in GBM cells, effects that were rescued by exogenous lactate supplementation. In vivo, OGDHL up-regulation inhibited tumor growth, reduced glutamate and lactate production, and decreased Ki-67- and PD-L1-positive cells, while increasing OGDHL-positive cells.

CONCLUSION: OGDHL exerts a tumor-suppressive function in GBM by regulating glutamine metabolism and histone lactylation-mediated PD-L1 expression, representing a potential new target for immunometabolic therapy.