Rabeprazole attenuates fibrosis by modulating SMAD3 linker region phosphorylation

Area of Science:

• Cell Biology
• Gastroenterology
• Pharmacology

Background:

• Epithelial-to-mesenchymal transition (EMT) and fibrosis are linked to TGFβ signaling.
• Rabeprazole is a proton pump inhibitor (PPI) used for *H. pylori* infection.
• The antifibrotic role of rabeprazole is not well understood.

Purpose of the Study:

• To investigate the potential antifibrotic effects of rabeprazole.
• To elucidate the mechanism by which rabeprazole influences fibrosis.
• To examine rabeprazole's impact on EMT in gastric epithelial cells.

Main Methods:

• Western blotting and RT-qPCR for gene expression analysis (mRNA and protein).
• Immunofluorescence, immunoprecipitation (IP), and dual luciferase reporter assays to determine mechanisms.
• Plasmid transfection for rescue experiments.

Main Results:

• Rabeprazole inhibited EMT in AGS and GES-1 cells.
• Rabeprazole upregulated transcriptional intermediary factor 1γ (TIF1γ) expression.
• TIF1γ upregulation decreased fibronectin (FN) and collagen type I alpha 1 chain (Col1a1) expression.
• Rabeprazole enhanced the interaction between TIF1γ and SMAD3, inhibiting SMAD3 phosphorylation and nuclear translocation.

Conclusions:

• Rabeprazole exhibits previously unrecognized antifibrotic activity.
• Rabeprazole's mechanism involves TIF1γ upregulation and SMAD3 interaction.
• Findings expand the known biological functions of rabeprazole and reveal a novel antifibrotic pathway.