Numb-exon3 and full length Numb equivalently alleviate cholestatic liver fibrosis by inhibiting ductular reaction

Cholestasis can occur in various acute and chronic liver diseases, with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) being the most common clinical manifestations. Without appropriate treatment, these conditions may ultimately progress to liver cirrhosis and hepatic failure. Therefore, identifying novel therapeutic targets is of great importance. Our previous research had found a gene target named Numb which is a determinant of stem cell fate can increase the anti-cholestatic liver fibrosis (CLF) effect of bone marrow mesenchymal stem cells (BM-MSCs). However, whether the Numb gene or its exon has direct anti-CLF activity is unclear. In this study, an adeno-associated virus (AAV) was used as a gene delivery vector to overexpress the full-length Numb gene directly in the rat liver. In addition, Exon3 was overexpressed to clarify the effective site of Numb gene for comparison. AAV.Numb can alleviate CLF and suppressed the activation of Notch signaling and the differentiation of hepatic progenitor cells (HPCs) into biliary epithelial cells (BECs), and the anti-CLF effect of Numb-Exon3 was similar to that of full-length Numb. The findings revealed that Numb gene may be a new therapeutic target for PBC and that Exon3 may be an effective site.