3-hydroxy-3-methylbutyrate (3H3MB) suppresses glioma growth and extends survival in mice

Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system, characterized by poor prognosis, limited therapeutic options, and a high rate of recurrence. A major contributor to its dismal clinical outcome is the highly invasive nature of glioblastoma cells, which infiltrate surrounding healthy brain parenchyma, precluding complete surgical resection and promoting therapeutic resistance. Emerging evidence suggests that the gut microbiota influences glioblastoma progression via modulation of neurotransmitter signaling and immune responses, and through alteration of microbial composition and metabolite production that impact tumor development. Building on our prior work demonstrating the relevance of the gut-brain axis in both physiological and glioma contexts, we identified a significant reduction in fecal levels of 3-hydroxy-3-methylbutyrate (3H3MB), a gut-associated leucine-derived metabolite that is chemically and metabolically distinct from the short-chain fatty acid butyrate, in glioma-bearing mice relative to their pre-tumor state. Given that 3H3MB administration has been reported to attenuate growth and proliferation in carcinoma models, we investigated its potential anti-tumor effects in glioma. In vivo, oral gavage of 3H3MB to glioma-bearing mice resulted in a significant reduction in tumor volume, decreased cellular proliferation, and prolonged overall survival compared to control animals. In vitro, 3H3MB markedly inhibited the proliferation of mouse glioma and human glioblastoma cell lines, modulating cell cycle phases; moreover, the treatment suppressed glioma cell migration and serum-induced invasion. These findings suggest that 3H3MB exerts robust anti-tumor effects in glioma-bearing mice and holds promise as a novel metabolic therapy for glioblastoma, supported by its established clinical evaluation in other pathological conditions.