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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1409001

Rabeprazole suppressed gastric intestinal metaplasia through activation of GPX4-mediated ferroptosis

Provisionally accepted
Jing Xie Jing Xie 1Fangfang Xie Fangfang Xie 1Xinhua Liang Xinhua Liang 1Zijun Lin Zijun Lin 1Shuping Xie Shuping Xie 1Fangying Yang Fangying Yang 1Fengfeng Zheng Fengfeng Zheng 2Lanlan Geng Lanlan Geng 1Wanfu Xu Wanfu Xu 1*Sitang Gong Sitang Gong 1Li Xiang Li Xiang 1
  • 1 Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, China
  • 2 Affiliated Hospital of Putian University, Putian, Fujian Province, China

The final, formatted version of the article will be published soon.

    Background. Gastric intestinal metaplasia is a common pathological feature in patients with Helicobacter pylori (H. pylori) infection. Rabeprazole was widely used as the first-line regimen for H. pylori infectious treatment. The objective of this study is to explore the mechanism of rabeprazole in gastric intestinal metaplasia treatment. Methods. Real-time PCR, western blotting (WB) and ROS analysis were conducted to confirm that rabeprazole could alleviate ferroptosis to suppress gastric intestinal metaplasia. cellular fraction, luciferase and chromatin immunoprecipitation (ChIP) were used to identify the mechanism underlying rabeprazole modulated ferroptosis. Results. Herein, we found rabeprazole treatment led to inhibit CDX2 and MUC2 expression, alleviating gastric intestinal metaplasia, which was attributed to enhanced ferroptosis characterized by decreased GPX4 expression. Inhibition of ferroptosis by ferrostatin-1 (Fer-1) could reverse decreased CDX2 and MUC2 expression caused by rabeprazole. Mechanically, Rabeprazole could inhibit CREB phosphorylation and nuclear translocation, which further decreased the binding of CREB to GPX4 promoter, reducing GPX4 transactivity. Moreover, endogenous PKA interacted with CREB, and this interaction was drastically destroyed in response to rabeprazole treatment. Most importantly, enhanced ferroptosis was observed in H. pylori-infected gastric intestinal metaplasia in comparison to HC control. Conclusion. These findings suggested that rabeprazole induced ferroptosis to reduce CDX2 expression in gastric epithelial cells through PKA/CREB cascade signaling, implying that targeting ferroptosis could be a promising strategy in improving gastric intestinal metaplasia during H. pylori-infected patients.

    Keywords: H. pylori, Gastric intestinal metaplasia, rabeprazole, ferroptosis, CREB

    Received: 29 Mar 2024; Accepted: 20 Sep 2024.

    Copyright: © 2024 Xie, Xie, Liang, Lin, Xie, Yang, Zheng, Geng, Xu, Gong and Xiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Wanfu Xu, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong Province, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.