Mangiferin targets PFKFB3 to inhibit glioblastoma progression by suppressing glycolysis and PI3K/AKT/mTOR signaling

Glioblastoma (GBM) is an aggressive and challenging primary brain tumor with poor prognosis despite advances in surgical resection, radiotherapy, and chemotherapy. Recently, targeting tumor cell metabolic pathways has emerged as a promising strategy for cancer treatment. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a key regulator of glycolysis and is overexpressed in GBM, promoting cell proliferation, migration, and survival. This study aims to evaluate the efficacy of the natural compound mangiferin in inhibiting GBM progression and elucidate its underlying mechanisms. Our screening of a natural compound library identified mangiferin as a potent PFKFB3 inhibitor. In vitro experiments demonstrated that mangiferin significantly inhibited the PI3K/AKT/mTOR signaling pathway by targeting PFKFB3, induced cell cycle arrest in the S phase, and promoted apoptosis in GBM cells. Additionally, mangiferin reduced glycolytic flux, inhibiting cell proliferation and migration. In vivo xenograft mouse models further validated the tumor-suppressive effects of mangiferin, with no observed systemic toxicity. These findings indicate that mangiferin exerts its antitumor effects on GBM by targeting PFKFB3, regulating tumor metabolism and growth. Mangiferin holds promise as a potential therapeutic candidate for the development of targeted therapies against GBM.