2. Academic Validation
  3. PRAG1 promotes cholangiocyte epithelial-mesenchymal transition and liver fibrosis in biliary atresia

PRAG1 promotes cholangiocyte epithelial-mesenchymal transition and liver fibrosis in biliary atresia

  • Biochim Biophys Acta Mol Basis Dis. 2025 Jul 29;1871(8):167994. doi: 10.1016/j.bbadis.2025.167994.
Wei Zhu 1,  Zhongxian Zhu 1,  Jie Feng 2,  Yao Lu 1,  Ruyi Zhang 1,  Zequan Ding 1,  Hua Xie 3,  Weibing Tang 4
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
  • 2 Laboratory of Contraceptives Vigilance and Fertility Surveillance, Jiangsu Provincial Medical Key Laboratory of Fertility Protection and Health Technology Assessment, Jiangsu Health Development Research Center, Nanjing 210008, China.
  • 3 Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address: xiehua3955@126.com.
  • 4 Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address: twbcn@njmu.edu.cn.
PMID: 40743806 DOI: 10.1016/j.bbadis.2025.167994
Abstract

Biliary atresia (BA) is a severe pediatric liver disease in which progressive liver fibrosis (LF) significantly affects the prognosis. Epithelial-mesenchymal transition (EMT) is considered a key factor in the development and progression of LF. This study aimed to investigate the role and mechanism of PEAK1-related kinase activating pseudokinase 1 (PRAG1) in the EMT-related LF process in BA. We found that the expression of PRAG1 was significantly elevated in both patients with BA and the bile duct ligation (BDL) model, and predominantly localized on biliary epithelial cells. Also, the expression of PRAG1 positively correlated with the cholangiocyte marker KRT19 and the mesenchymal marker ACTA2, and increased with the severity of fibrosis. In human intrahepatic biliary epithelial cells (HIBECs), PRAG1 promoted the expression of mesenchymal markers (VIM and ACTA2) and fibrosis markers (COL1A1 and FN1), inhibited the expression of the epithelial marker CDH1, and enhanced cell proliferation. The key factor of EMT-SNAIL1 presented increased expression and delayed degradation after overexpression of PRAG1. Moreover, we identified PRAG1 could bind with F-box protein 11 (FBXO11) and subsequently reversed FBXO11-mediated inhibition of SNAIL1 protein expression, cell proliferation, and the EMT phenotype. This study provides the potential role of PRAG1 in the mechanisms underlying the LF progression of BA.

Keywords

Biliary atresia; Epithelial-mesenchymal transition; FBXO11; Liver fibrosis; PRAG1; SNAIL1.

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