β‐Sitosterol suppresses hepatocellular carcinoma growth and metastasis via FOXM1‐regulated Wnt/β‐catenin pathway

Abstract 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. In this study, we investigated the effects of β‐sitosterol on HCC tumour 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. The results found that 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 signalling by downregulating FOXM1, regulating target gene transcription related to HepG2 cell proliferation and metastasis. β‐Sitosterol shows promising potential as a therapeutic candidate for inhibiting HCC growth and metastasis through FOXM1 downregulation and Wnt/β‐catenin signalling inhibition.