Tumor-Intrinsic HEXB Drives Endothelial-To-Mesenchymal Transition and Confers Resistance to Anti-Angiogenic Therapy in Glioblastoma.

Although anti-angiogenic (anti-VEGF) therapy is widely used for glioblastoma (GBM), its efficacy is severely limited by acquired resistance. Here, we identify endothelial-mesenchymal transition (Endo-MT) in brain endothelial cells as the primary driver of this resistance, fundamentally modulated by hexosaminidase B (HEXB). Mechanistically, HEXB directly binds and stabilizes heat shock protein 60 (HSP60) by inhibiting its ubiquitination and degradation. This stabilization upregulates insulin-like growth factor binding protein 1 (IGFBP1), thereby promoting the Endo-MT process. Addressing its clinical relevance, the combination of a HEXB inhibitor and anti-VEGF therapy exerts potent synergistic therapeutic effects in GBM murine models. Overall, our study establishes HEXB as a key driver of Endo-MT and provides a promising dual-targeting strategy to overcome anti-VEGF resistance in GBM.