Brusatol inhibits malignant phenotypes and lipid metabolism of osteosarcoma cells by regulating PI3K/AKT and MAPK pathways

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 BRUtreated 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.