Xiao Shilang, Shen Yicun, Zhang Minglin, Liu Xiaoming, Cai Ting, Wang Fen
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China; Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, Changsha, China.
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, Hunan 410013, China; Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, Changsha, China.
Microbiol Res. 2025 Jul;296:128142. doi: 10.1016/j.micres.2025.128142. Epub 2025 Mar 20.
Atrophic gastritis (AG) is a chronic inflammation where gastric glandular cells are replaced by intestinal-type epithelium. Gastric epithelial cell loss is often linked to multiple cell death signaling pathways. While Helicobacter pylori (H. pylori) infection is the main cause of AG, its role in inducing cell death goes beyond apoptosis and autophagy. Pyroptosis could promote development of inflammation related cancers, but its involvement in H. pylori-induced malignant transformation remains unclear.
The enrichment of pyroptosis signaling across pathological stages was assessed using immunohistochemistry and bioinformatic analysis. Gastric epithelial cells were co-cultured with VacA recombinant protein or VacAH. pylori to investigate the role of VacA in pyroptosis, and its downstream targets. TNFAIP3 or TRAF1 was silenced/overexpressed in gastric epithelial cells to explore their impact on pyroptosis. Finally, the interaction between TNFAIP3 and TRAF1 was examined using Western Blot, immunofluorescence, co-immunoprecipitation and ubiquitin assays.
Expression of pyroptosis components and pyroptosis enrichment score were upregulated in AG and gastric cancer tissues compared to normal or non-atrophic gastritis tissues. Upon incubation with VacA recombinant protein or VacAH. pylori, pyroptosis and TNFAIP3/TRAF1 were elevated in gastric epithelial cells. TRAF1 promoted expression of downstream pyroptosis components and release of IL-1β/IL18. TRAF1 ablation could reverse pyroptosis activation caused by VacA. Finally, we proved TNFAIP3 as deubiquitinating enzyme to increase TRAF1 stability, further inducing pyroptosis.
The VacA/TNFAIP3/TRAF1 signaling cascade facilitates pyroptosis in H. pylori- infected tissue. Overactivation of Pyroptosis caused the atrophy-like morphological changes of gastric epithelium, further inducing sustainable malignant transformation.
