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Calcipotriol abrogates TGF-β1/pSmad3-mediated collagen 1 synthesis in pancreatic stellate cells by downregulating

Meifang Zheng1, Hongyan Li1, Li Sun1

  • 1Department of Hepatic biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China.

Toxicology and Applied Pharmacology
|August 30, 2024
PubMed

Insights

RUNX1 activates collagen synthesis in pancreatic stellate cells via the TGF-β1/pSmad3 pathway. Calcipotriol inhibits this process by downregulating RUNX1, suggesting RUNX1 as a potential antifibrotic target for pancreatitis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Gastroenterology

Background:

  • RUNX1, in complex with CBFβ, regulates key cellular functions.
  • Transforming growth factor-beta 1 (TGF-β1) is implicated in fibrotic processes.
  • Pancreatic stellate cells (PSCs) play a central role in pancreatic fibrosis.

Purpose of the Study:

  • To elucidate RUNX1's role in TGF-β1-induced collagen type 1 (COL1) synthesis in PSCs.
  • To investigate the mechanism by which calcipotriol (Cal) antagonizes COL1 synthesis.
  • To identify potential antifibrotic therapeutic targets for chronic pancreatitis.

Main Methods:

  • Quantitative real-time PCR (RT-qPCR) and Western blotting for RUNX1 and COL1A1/1A2.
  • Luciferase reporter assays for promoter activity.
  • Co-immunoprecipitation and immunoblotting for protein interactions (pSmad3/RUNX1, CBFβ/RUNX1).
  • Gene knockdown and upregulation experiments for Smad3 and RUNX1.

Main Results:

  • TGF-β1/pSmad3 signaling pathway regulates RUNX1 production in PSCs.
  • RUNX1 and CBFβ form a coactivator complex (pSmad3/RUNX1/CBFβ) that drives COL1A1/1A2 transcription.
  • Calcipotriol inhibits COL1A1/1A2 transcript levels by reducing RUNX1 and disrupting the pSmad3/RUNX1/CBFβ complex formation.

Conclusions:

  • RUNX1 is a key regulator of TGF-β1-induced collagen synthesis in pancreatic stellate cells.
  • Calcipotriol's antifibrotic effect is mediated through the downregulation of RUNX1 and its coactivator complex.
  • RUNX1 represents a promising antifibrotic therapeutic target for chronic pancreatitis.
Keywords:
Anti-Pancreatic FibrosisCalcipotriolPancreatic Stellate CellRUNX1TGF-β1

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