Mechanistically, HF dose-dependently activated the SIX4/AKT/STAT3 signaling axis both in vitro and in vivo; siRNA-mediated SIX4 knockdown or pharmacological STAT3 inhibition (S3I-201) in HepG2 cells markedly attenuated HF’s protective effects, while immunohistochemical analysis of liver tissue from HF-treated mice demonstrated increased phospho-STAT3 nuclear translocation, underscoring this pathway’s centrality in HF’s hepatoprotective mechanism. The gene discussed is SIX4; the disease is hydrops fetalis.