# Nitrate Enhances Gastric Mucosa Defense and Repair Process in Ethanol‐Induced Gastric Ulcer Rats via the Notch–Tff2 Pathway

## TL;DR

Nitrate helps protect the stomach lining from ethanol damage in rats by enhancing repair processes through the Notch–Tff2 pathway.

## Contribution

This study reveals TFF2 as a central effector in nitrate-mediated gastric mucosal defense and repair, implicating the Notch signaling pathway.

## Key findings

- Nitrate reduces ethanol-induced gastric bleeding, edema, and inflammation in rats.
- TFF2 is a key mediator of nitrate's protective effects and is regulated by the Notch signaling pathway.
- Nitrate promotes gastric epithelial cell migration, aiding ulcer repair.

## Abstract

Gastric mucosal integrity is essential for maintaining systemic homeostasis, serving as the primary defense against external insults. Ethanol ingestion is a major clinical cause of gastric mucosal injury, yet effective prevention or treatment remains limited. This study investigates the protective role of nitrate against ethanol‐induced gastric ulcers and its underlying mechanisms. In vivo, nitrate significantly ameliorated ethanol‐induced gastric bleeding, edema, inflammation, and mucus layer thinning in rats, while strengthening the vascular endothelial barrier. Transcriptomic analyses and trefoil factor 2 (Tff2)‐knockdown rats experiment identified Tff2 as the key gene responsible for mediating nitrate's protective effects against ethanol. In vitro, TFF2 was found to be a crucial target for nitrates, which enhance the migratory reparative capacities of human gastric epithelial cells. Further assays revealed that RBPJ regulates the TFF2 promoter, and NICD–RBPJ complex formation is critical for TFF2 transcriptional repression. We demonstrate for the first time that TFF2 is a central effector in nitrate‐mediated gastric mucosal defense and repair and implicate the Notch signaling pathway in TFF2 regulation. These findings suggest nitrate exerts a protective effect on the gastric mucosa through multiple ways. TFF2 modulation as a potential preventive strategy for ethanol‐induced gastric ulcers.

Nitrate protects the three major barriers of the gastric mucosa, alleviating bleeding and inflammation of ethanol‐induced gastric ulcer in rats, and promotes migration of gastric epithelial cells, accelerating the restoration of the ulcerated epithelium, which is strongly related to TFF2, a gastric mucosal protective factor negatively regulated by the Notch signaling pathway.