FOXM1 knockdown suppresses hepatoblastoma progression and glycolysis by inhibiting the Wnt/β-catenin pathway

BACKGROUND: Hepatoblastoma (HB) ranks as the predominant primary malignant neoplasm affecting the pediatric liver, yet effective targeted therapies remain limited. Forkhead box M1 (FOXM1) is a pivotal oncogenic transcription factor overexpressed in multiple malignancies, but its role in HB metabolic reprogramming and the underlying mechanisms remain poorly understood. METHODS: Glycolysis-related hub genes in HB were pinpointed by leveraging integrated bioinformatic analysis of datasets obtained from the Gene Expression Omnibus. FOXM1 expression was silenced using siRNA in HepG2 and Huh6 cells, and its effects on cell proliferation, apoptosis, migration, invasion, and glycolytic activity were assessed by Cell Counting Kit-8, flow cytometry, Transwell assays, and metabolite measurements, respectively. The involvement of Wnt/beta-catenin (β-catenin) signaling was evaluated using the pathway agonist SKL2001. An in vivo xenograft model was employed to assess the influence of FOXM1 suppression on tumor growth. RESULTS: FOXM1 was identified as a core glycolysis-associated hub gene in HB. FOXM1 knockdown significantly reduced cell viability, induced apoptosis, and impaired migration, invasion, and glycolytic activity in HB cells, accompanied by decreased expression of Glucose Transporter Type 1 (GLUT-1) and Lactate Dehydrogenase A (LDHA). In vivo, FOXM1 silencing suppressed tumor growth, GLUT-1 expression, and lactate production. Mechanistically, FOXM1 knockdown decreased β-catenin and Wnt5a protein levels, effects partially reversed by SKL2001, which also restored the malignant phenotype and glycolytic capacity suppressed by FOXM1 silencing. CONCLUSIONS: FOXM1 silencing suppresses HB progression and glycolysis at least in part through inhibition of the Wnt/β-catenin pathway, highlighting FOXM1 as a potential therapeutic target for this aggressive pediatric cancer.