SMAD3 and Hepatic fibrosis: Furthermore, the overexpression of L-HDAg resulted in a significant increase in Akt2 expression, decrease in NF1 expression and upregulation of Twist downstream fibrosis promoting genes Serpin1 and TIMP1. This study not only found that L-HDAg has been reported to bind and activate SMAD3 consistent with the previous report [12], but also reported for the first time that L-HDAg can activate Twist through its interaction with SMAD3 and further contribute to EMT and the subsequent liver fibrosis.