{
  "abstract": "Background The molecular mechanisms linking bile acid signaling to biliary fibrosis in hepatolithiasis are unclear. We investigated the role of the bile acid receptor TGR5 in driving fibrotic progression.Methods We employed an integrated strategy. TGR5 expression was assessed in human hepatolithiasis tissues and bioinformatics databases. A hepatolithiasis mouse model was compared with TGR5-knockout (TGR5-/-) mice, analyzing lipid metabolism, cholesterol transport, and fibrosis markers via ELISA, qPCR, and immunohistochemistry. In vitro, human intrahepatic biliary epithelial cells (HIBECs) were treated with bile acids, TGR5 agonists/inhibitors, and cAMP modulators. We assessed the cAMP/PKA/CREB pathway, epithelial-mesenchymal transition (EMT), and fibrosis.Results TGR5 was significantly overexpressed in hepatolithiasis tissues. Genetic deletion of TGR5 in mice alleviated metabolic disturbances and markedly reduced fibrosis markers (TGF-β1, α-SMA, Collagen I) ( IDDF2026-ABS-0217 Figure 1). In cholangiocytes, TGR5 activation stimulated the cAMP/PKA/CREB signaling cascade, promoting EMT and fibrosis. These pro-fibrotic effects were reversed by inhibiting TGR5 or cAMP. Mechanistically, TGR5-driven cAMP signaling induced CREB phosphorylation, leading to upregulated TGF-β1 expression, which sustains the fibrotic phenotype (IDDF2026-ABS-0217 Figure 2, IDDF2026-ABS-0217 Figure 3, IDDF2026-ABS-0217 Figure 4, IDDF2026-ABS-0217 Figure 5, IDDF2026-ABS-0217 Figure 6).Conclusions This study defines a critical pathogenic axis in hepatolithiasis, whereby TGR5 activation in cholangiocytes triggers cAMP/PKA/CREB signaling to promote EMT and biliary fibrosis via TGF-β1. Our findings directly implicate TGR5 as a central therapeutic target for mitigating fibrosis in this disease.Abstract IDDF2026-ABS-0217 Figure 1Abstract IDDF2026-ABS-0217 Figure 2Abstract IDDF2026-ABS-0217 Figure 3Abstract IDDF2026-ABS-0217 Figure 4Abstract IDDF2026-ABS-0217 Figure 5Abstract IDDF2026-ABS-0217 Figure 6",
  "authors": [
    {
      "affiliations": [
        "Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Dan Tang"
    },
    {
      "affiliations": [
        "Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Jiali Yang"
    },
    {
      "affiliations": [
        "Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Xinhao Shi"
    },
    {
      "affiliations": [
        "Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Xuanyu Gu"
    },
    {
      "affiliations": [
        "Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, China"
      ],
      "name": "Lijin Zhao"
    }
  ],
  "title": "IDDF2026-ABS-0217 Activation of the TGR5/cAMP/PKA/CREB Axis in cholangiocytes mediates epithelial-mesenchymal transition and fibrosis in hepatolithiasis",
  "uid": "977cc8c7-daf8-59fb-8579-2083458b9e1d"
}