ObjectiveTo elucidate the mechanism of orlistat in reversing bevacizumab resistance in glioblastoma (GBM), focusing on its regulation of the SREBP-1/FASN lipogenic pathway and epithelial-mesenchymal transition (EMT).MethodsCommon targets of orlistat and GBM were screened via bioinformatic databases for PPI network and enrichment analyses. The effects of orlistat on bevacizumab-resistant GBM cells (U87, U251, SHG-44) were examined in vitro: proliferation (MTT assay), migration/wound healing, invasion/Transwell; intracellular triglyceride (TG) content (ELISA); mRNA and protein expression of lipid metabolism (SREBP-1, FASN) and EMT (E-cadherin, N-cadherin, Vimentin, SNAI2) markers (qPCR, Western blot).ResultsWe identified 45 intersection targets. Topological analysis revealed SREBF1, FASN, and EGFR as core targets, significantly enriched in fatty acid biosynthesis, PI3K-AKT/MAPK signaling, and EMT pathways. Orlistat treatment dose-dependently dampened cell viability, migration, and invasion (P<0.05), decreased TG levels, upregulated E-cadherin, and downregulated N-cadherin, Vimentin, and SNAI2. It concomitantly inhibited SREBP-1 and FASN protein expression.ConclusionOrlistat overcomes bevacizumab resistance in GBM by inhibiting SREBP-1/FASN-mediated lipogenesis and reversing EMT, providing a promising metabolic-based therapeutic strategy against targeted therapy resistance.