HELICOBACTER PYLORI-INDUCED FERROPTOSIS CONTRIBUTES TO ATROPHIC GASTRITIS VIA MODULATING SELENIUM UTILIZATION BY GPX4.

BACKGROUND: Helicobacter pylori (H. pylori) infection is widely recognized as the most potent risk factor for the development of gastric cancer. H. pylori-induced atrophic gastritis, characterized by the presence of atrophy and metaplasia, has been identified as a precancerous lesion. However, the precise mechanism underlying this process has not been fully elucidated. Ferroptosis, a form of cell death induced by iron-dependent lipid peroxidation, has been reported in some infectious diseases. H. pylori infection evokes the production of reactive oxygen species. Nevertheless, the relationship between ferroptosis and H. pylori-induced atrophic gastritis remains largely unknown.
METHODS: H. pylori infected C57BL/6J mice and GES-1 cells were utilized for in vivo and in vitro studies, respectively. Gastric lesions from patients and mouse models were collected to analyze H. pylori infection, ferroptosis, atrophy and metaplasia using ELISA, immunohistochemical staining and transmission electron microscopy. Polyribosome fractionation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro.
RESULTS: Gastric mucosa atrophy and metaplasia exhibited a strong correlation with ferroptosis in the human stomach. H. pylori infection induced gastric epithelial cell ferroptosis both in vitro and in vivo. Notably, pharmaceutical inhibition of ferroptosis by Liproxstatin-1 successfully mitigated the inflammation, atrophy, and metaplasia induced by H. pylori. Mechanistically, H. pylori impaired the synthesis efficiency of Glutathione peroxidase 4 (GPX4) by limiting selenocystine incorpration, resultinig in decreased GPX4 protein levels. Further investigation revealed that H. pylori suppresses endocytosis of selenoprotein P miediated by low-density lipoprotein receptor-related protein 1 (LRP1), thereby influencing selenium uptake.
CONCLUSIONS: Our study revealed a novel mechanism of H. pylori-induced atrophic gastritis involving the LRP1-selenium-GPX4 axis mediated ferroptosis. The results of our study indicate that selenium supplement could be a promising preventive therapeutic strategy for H. pylori-induced atrophic gastritis.