FUCA1-Mediated Metabolic Adaptation Facilitates Lactylation-Induced Vasculogenic Mimicry in Glioblastoma

Abstract

Vasculogenic mimicry (VM) is a process in which malignant cells acquire endothelial-like functions to generate perfusable vascular channels independent of endothelial cells. VM represents a major barrier to effective vascular endothelial growth factor A (VEGFA)-targeted therapy in cancer. In this study, we used organ-scale vascular imaging that identified a mechanism of VM in glioblastoma (GBM) mediated by alpha-L-fucosidase 1 (FUCA1). FUCA1 was preferentially expressed in glioblastoma stem-like cells (GSCs) with high CD44 expression. FUCA1 functioned as a key regulator of GSC-mediated VM by stabilizing LDHA protein and promoting a metabolic shift toward glycolysis. Elevated glycolytic flux increased lactate production and enhanced histone H3 lysine 18 lactylation (H3K18la), which in turn activated SERPINF1 transcription and drove VM in GSCs. In preclinical models, the FUCA1 inhibitor deoxyfuconojirimycin hydrochloride (DFH) significantly reduced GSC tumorigenicity and VM in vivo and exhibited robust antitumor activity when combined with anti-VEGFA therapy. Collectively, these findings define a FUCA1-mediated histone lactylation pathway that enhances GSC VM and highlight a therapeutically targetable mechanism to improve the efficacy of current anti-angiogenic strategies in GBM.