β-Sitosterol Suppresses Hepatocellular Carcinoma Growth and Metastasis via FOXM1-Regulated Wnt/β-Catenin Pathway

Background: and Purpose: β-Sitosterol is a natural compound with demonstrated anti-cancer properties against various cancers. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms are not well understood. This study aims to investigate the impact of β-sitosterol on HCC tumor growth and metastasis and identify potential targets for the treatment of HCC. Experimental Approach: We investigated the effects of β-sitosterol on HCC tumor growth and metastasis using a xenograft mouse model and a range of molecular analyses, including bioinformatics, real-time PCR, western blotting, lentivirus transfection, CCK8, scratch, and Transwell assays. Key Results: β-Sitosterol significantly inhibits HepG2 cell proliferation, migration, and invasion both in vitro and in vivo. Bioinformatics analysis identifies forkhead box M1 (FOXM1) as a potential target for β-sitosterol in HCC treatment. FOXM1 is upregulated in HCC tissues and cell lines, correlating with poor prognosis in patients. β-sitosterol downregulates FOXM1 expression in vitro and in vivo. FOXM1 overexpression mitigates β-sitosterol’s inhibitory effects on HepG2 cells. Additionally, β-sitosterol suppresses Epithelial-Mesenchymal Transition (EMT) in HepG2 cells, while FOXM1 overexpression promotes EMT. Mechanistically, β-sitosterol inhibits Wnt/β-catenin signaling by downregulating FOXM1, regulating target gene transcription related to HepG2 cell proliferation and metastasis. Conclusions & Implications: β-Sitosterol shows promising potential as a therapeutic candidate for inhibiting HCC growth and metastasis through FOXM1 downregulation and Wnt/β-catenin signaling inhibition.