Targeting FOXM1/Cystathionine-β-Synthase Axis by Brusatol Inhibits Lung Cancer Malignant Progression

Brusatol (BRU), an extract derived from Brucea javanica, has been shown to exert antitumor effects on various cancers, including lung cancer. However, its downstream molecular targets and the underlying mechanisms in lung cancer remain to be fully elucidated. Label-free quantitative proteomic analysis was used to identify the altered proteins in response to Brusatol treatment. The colony formation, Propidium iodide (PI) staining, and CCK8 were applied to detect cell proliferation, apoptosis, and cytotoxicity. Western blot and qRT-PCR were used to detect the expression of FOXM1 and CBS. The interaction between Brusatol and FOXM1 was validated by Streptavidin (SA)-based pulldown, Cellular Thermal Shift Assay, and molecular docking. In this study, we demonstrated that Brusatol directly interacts with FOXM1, leading to its degradation, thereby suppressing the malignant progression of lung cancer both in vitro and in vivo. Furthermore, our findings revealed that FOXM1 binds to the promoter region of Cystathionine beta-synthase (CBS) and enhances its expression in lung cancer cells. In addition, we evaluated the antitumor effects of Brusatol using a patient-derived organoid (PDO) model of lung cancer and observed that Brusatol significantly reduced cell viability, induced cell death, and downregulated the expression of both FOXM1 and CBS in PDOs. Moreover, a positive correlation between FOXM1 and CBS expression was identified in lung cancer. Taken together, our results indicate that Brusatol functions as a novel FOXM1 inhibitor and inhibits lung cancer progression by blocking the activation of the FOXM1/CBS signaling axis.