The present study observed the effects of β-hydroxybutyrate (β-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in β-OHB-regulated FGF21 expression was investigated. The gene discussed is FGF21; the disease is hepatocellular carcinoma.