Rabeprazole destroyed gastric epithelial barrier function through FOXF1/STAT3‐mediated ZO‐1 expression

Abstract

Rabeprazole is a representative of proton pump inhibitors and widely used in antiulcer treatment. However, the effect of Rabeprazole on gut barrier function remains to be identified. In this study, we show that ZO-1 expression is decreased in patients receiving Rabeprazole by immunofluorescence (IF) analysis. Western blotting (WB) and real-time PCR (qPCR) results demonstrate that Rabeprazole treatment leads to a significant downregulation of ZO-1 expression through inhibition of the FOXF1/STAT3 pathway, leading to destroy barrier function, which illustrates a novel pathway that Rabeprazole regulates barrier function in gastric epithelial cells. Mechanistically, Rabeprazole treatment led to a downregulation of STAT3 and FOXF1 phosphorylation, leading to inhibit nuclear translocation and decrease the binding of STAT3 and FOXF1 to ZO-1 promoter, respectively. Most important, endogenous FOXF1 interacted with STAT3, and this interaction was dramatically abolished by Rabeprazole stimulation. Overexpression of STAT3 and FOXF1 in GES-1 cells reversed the inhibitory effect of Rabeprazole on ZO-1 expression, respectively. These finding extended the function of Rabeprazole and established a previously unappreciated mechanism by which the Rabeprazole/FOXF1/STAT3 axis facilitated ZO-1 expression to regulate barrier function, and a comprehensive consideration and evaluation was required in treatment of patients.

Trypsin activates PAR2 inhibits the expression of tight junction protein through activation of NLRP3 inflammasome pathway in gastroesophageal reflux disease

“…The involvement of non-classical pathways of cellular pyroptosis and other pathways may exist in this pathologic process. Rabeprazole treatment regulates ZO-1 expression in the gastric mucosa via the forkhead box F1/signal and the transcription 3 pathway [32] . PPIs may differentially affect the mucosal barrier by altering the composition of the gut microbiota [33] .…”

Suppression of cell pyroptosis by omeprazole through PDE4-mediated autophagy in gastric epithelial cells

“…Recently, more and more work about the function of PPI in gastrointestinal function has been reported. The previous studies from our lab have demonstrated that another PPI, rabeprazole, inhibited gastric epithelial cell proliferation, which was attributed to the inhibitory effect of Rabeprazole on Signal transducer and activator of transcription 3 (STAT3)-mediated glycolysis (Zhou et al, 2021), further work showed that rabeprazole inhibited cell pyroptosis, leading to decrease inflammatory reaction (Xie et al, 2021), and destroyed gastric barrier function by inhibition of FOXF1/STAT3-mediated ZO-1 expression (Yang et al, 2023). In addition to rabeprazole, we also demonstrated that omeprazole suppressed de novo lipogenesis in gastric epithelial cells by reducing fatty acid synthase and ATP citrate lyase expression (Chen et al, 2020).…”