Targeting glioblastoma with metabolic drugs highlighted R-sodium lipoate as a potent therapeutic approach

Abstract Glioblastoma (GBM) is an aggressive and lethal malignant brain tumor with a median survival of approximately 18 months after diagnosis. GBMs display extensive cellular and molecular heterogeneity, which critically contributes to poor patient outcomes. The metabolic adaptive programs employed by highly plastic and aggressive GBM subtypes in response to their microenvironment are key drivers of disease progression and relapse. Therefore, targeting this metabolic flexibility is essential for effective GBM treatment. In this study, we screened eight well-characterized metabolic drugs targeting GBM metabolism across multiple paired patient-derived differentiated (GDC) and stem cell (GSC) cell lines, identifying R-sodium-lipoate (R-LA) as the most potent and broadly effective inhibitor of GBM aggressiveness and cell-death inducer. Kinomic profiling under R-LA treatment revealed a broad inhibitory effect on kinase activities, while Seahorse analyses, functional tracing and metabolomic studies demonstrated significant modulation of GBM cell metabolism. Finally, R-LA-treatment significantly prolonged survival in GBM-bearing mice, highlighting its therapeutic potential as a metabolic-targeting drug in GBM management.