BACKGROUND: Osteosarcoma (OS), the most frequent type of primary bone cancer, has a poor prognosis in metastatic cases, with overall 5-year survival rates stagnating at 20 %-30 %. This highlights the critical need for innovative therapies to address the significant survival gap between metastatic and non-metastatic cases. Brusatol (BRU), a compound extracted from Brucea javanica, has shown promising anti-tumor properties in various cancers
however, its effects on OS have yet to be investigated. PURPOSE: To investigate the anti-tumor mechanisms of BRU in OS and evaluate its potential therapeutic efficacy, with a particular focus on its impact on lipid metabolism and related signaling pathways. METHODS: In vitro experiments to assess the anti-tumor effects of BRU involved colony formation, CCK-8, Transwell analysis, as well as flow cytometry. RNA sequencing was conducted to identify transcriptional changes in BRU-treated cells. The mechanism of action was investigated through analysis of lipid metabolism and key signaling pathways. Therapeutic efficacy and safety were evaluated in vivo using xenograft models. RESULTS: BRU significantly inhibited OS cell proliferation, migration, and invasion, while also inducing G2/M phase cell cycle arrest as well as promoting apoptosis. Transcriptome analysis revealed that BRU affected lipid metabolism-related genes and suppressed the PI3K/AKT and MAPK pathways. BRU treatment reduced fatty acid synthase expression and free fatty acid content in OS cells. In vivo experiments demonstrated that BRU effectively restricted xenograft growth. CONCLUSION: This study revealed that BRU exhibits potent anti-tumor effects in OS by modulating lipid metabolism through the PI3K/AKT and MAPK pathways.