Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality. Despite rapid progress in targeted therapy and immunotherapy for HCC over the past 10 years, the overall efficacy remains unsatisfactory. This is mainly due to the presence of an intrahepatic microenvironment of cirrhosis in HCC patients, leading to cancer recurrence and drug resistance.In this study, we investigated the correlations between the Wnt-1/β-catenin signaling pathway and the prognosis as well as liver function of HCC patients. Additionally, we conducted in vitro experiments using different concentrations of matrine on HuH-7 cells. Furthermore, we verified the associations between the Wnt-1/β-catenin signaling pathway, inflammation, and epithelial-mesenchymal transition (EMT) in a rat model of pre-hepatocellular carcinoma. Finally, matrine was employed to treat pre-hepatocellular carcinoma in rats and patients with advanced hepatocellular carcinoma.The results demonstrated the activation of the Wnt-1/β-catenin signaling pathway, the occurrence of EMT, and exacerbated inflammation in human HCC tissues. In HuH-7 cell experiments, matrine effectively downregulated the Wnt-1/β-catenin pathway, reversed EMT, and suppressed migration and invasion of HCC cells. In the rat model of pre-hepatocellular carcinoma, matrine dose-dependently inhibited the activation of the Wnt-1/β-catenin signaling pathway, reversed the occurrence of EMT, and alleviated liver inflammation. Matrine analogues exhibited promising hepatoprotective effects in patients with advanced HCC.Matrine can reverse EMT, alleviate intrahepatic inflammation, and counteract immune depletion by inhibiting the Wnt-1/β-catenin signaling pathway in HCC.AJTR Copyright © 2023.