In conclusion, lenvatinib activates AZGP1 by increasing the acetylation level of H3K27Ac on the AZGP1 promoter region and regulates the TGF-β1/Smad3 signaling pathway in an AZGP1-dependent manner to inhibit ICC-EMT. This evidence concerns the gene SMAD3 and intrahepatic cholangiocarcinoma.