2. Academic Validation
  3. A novel triazole derivative ameliorates ethanol-induced gastric ulcer via a NOS2-centered inhibition of the AGE-RAGE pathway

A novel triazole derivative ameliorates ethanol-induced gastric ulcer via a NOS2-centered inhibition of the AGE-RAGE pathway

  • Int Immunopharmacol. 2026 Mar 1:172:116240. doi: 10.1016/j.intimp.2026.116240.
Cong Xie 1,  Jiahui Yue 2,  Wenying He 3,  Changbin Yu 4
Affiliations

Affiliations

  • 1 Jinan Central Hospital Affiliated to Shandong First Medical University, No. 105 Jiefang Road, Jinan 250000, Shandong, China; Shandong First Medical University(Shandong Academy of Medical Sciences), Jinan 250000, Shandong, China.; Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, Hainan, China.
  • 2 School of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan 751104, Ningxia, China; Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia, China.
  • 3 Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, Hainan, China.
  • 4 Jinan Central Hospital Affiliated to Shandong First Medical University, No. 105 Jiefang Road, Jinan 250000, Shandong, China; Shandong First Medical University(Shandong Academy of Medical Sciences), Jinan 250000, Shandong, China.. Electronic address: [email protected].
PMID: 41576570 DOI: 10.1016/j.intimp.2026.116240
Abstract

Ethanol-induced gastric ulcer, driven by intricate inflammatory and oxidative stress pathways, lacks optimally effective treatments. Utilizing an integrated approach combining network pharmacology and experimental validation in vivo using a mouse model and in vitro with gastric epithelial cells, this study elucidates the gastroprotective mechanism of the compound MPTA. Network pharmacology identified NOS2 as a central hub gene, guiding subsequent experimental investigation. In an ethanol-induced ulcer mouse model, MPTA administration dose-dependently ameliorated gastric mucosal damage, suppressed pro-inflammatory cytokines including TNF-α, IL-6, IL-1β and IL-8, elevated TGF-β and NO levels, and reduced oxidative stress; these protective effects were attenuated by a NOS2 inhibitor. Proteomic and molecular analyses demonstrated that MPTA downregulated the AGE-RAGE/NF-κB/p38 MAPK inflammatory pathway and activated the NRF2/HO-1/SOD2 antioxidant axis. In vitro, MPTA enhanced cell viability and migration while diminishing Apoptosis and ROS accumulation in gastric epithelial cells, primarily through NOS2-centered regulation of the AGE-RAGE signaling pathway. We conclude that MPTA protects against ethanol-induced gastric injury by inhibiting NOS2 to mitigate inflammatory and oxidative stress via the AGE-RAGE pathway. This study unveils a novel gastroprotective mechanism centered on the downregulation of NOS2, underscoring its potential as a protective candidate for ethanol-induced gastric ulcer.

Keywords

AGE-RAGE; Ethanol-induced gastric ulcer; Inflammation; NOS2; ROS; Triazole.

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