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

## TL;DR

This study shows that both full-length Numb and its Exon3 can reduce liver fibrosis caused by cholestasis by inhibiting cell differentiation.

## Contribution

The study demonstrates that Numb Exon3 is as effective as full-length Numb in alleviating cholestatic liver fibrosis.

## Key findings

- Overexpression of full-length Numb or Exon3 reduces cholestatic liver fibrosis in rats.
- Numb suppresses Notch signaling and differentiation of hepatic progenitor cells into biliary epithelial cells.
- Exon3 is identified as an effective functional site of the Numb gene for anti-fibrotic effects.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-025-23696-3.