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

  • MedComm (2020). 2026 Feb 5;7(2):e70628. doi: 10.1002/mco2.70628.
Ying Liu  1  2 ,  Xin Wen  1  2 ,  Yuxuan Lin  1  2 ,  Chunmei Zhang  1  2 ,  Jinsong Wang  1  3 ,  Guangyong Sun  1  2  4 ,  Dong Zhang  1  2  4 ,  Renhong Yan  5  6 ,  Mo Chen  7 ,  Songlin Wang  1  2  3  8  9 ,  Shaorong Li  1  2  10
Affiliations
  • 1. Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and School of Stomatology, Capital Medical University Beijing China.
  • 2. Immunology Research Center For Oral and Systemic Health Beijing Friendship Hospital, Capital Medical University Beijing China.
  • 3. Department of Biochemistry and Molecular Biology School of Basic Medical Sciences, Capital Medical University Beijing China.
  • 4. Medical Research Center Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University Beijing China.
  • 5. Department of Biochemistry School of Medicine, Southern University of Science and Technology Shenzhen Guangdong Province China.
  • 6. Key University Laboratory of Metabolism and Health of Guangdong, SUSTech Homeostatic Medicine Institute, Institute for Biological Electron Microscopy, Southern University of Science and Technology Shenzhen Guangdong Province China.
  • 7. Department of Pharmacology Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine and SUSTech Homeostatic Medicine Institute, Southern University of Science and Technology Shenzhen China.
  • 8. Laboratory For Oral and General Health Integration and Translation Beijing Tiantan Hospital, Capital Medical University Beijing China.
  • 9. Laboratory of Homeostatic Medicine School of Medicine, Southern University of Science and Technology Shenzhen China.
  • 10. Department of Endodontics School of Stomatology Capital Medical University Beijing China.
PMID: 41660303 DOI: 10.1002/mco2.70628
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.

Keywords
Notch; epithelial restitution; ethanol; gastric mucosal barrier; migration; trefoil factor 2.
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