Our current findings illustrate that upregulated IQGAP3 expression promotes TGF-β1 expression in HCC cells, and TGF-β1 activation results in Smad2 and Smad3 phosphorylation, leading to upregulation of multiple downstream genes including TGFB1, MMP2, LTBP1, and THBS1. In the nude mice model, western blot showed that IQGAP3 overexpression was significantly correlated with high Snail, Twist1, MMP2, and MMP9 expression. Here, SMAD2 is linked to hepatocellular carcinoma.