DNMT1/MTTP axis promotes gastritis progression during Helicobacter pylori infection by regulating GPX4 and ferroptosis

Helicobacter pylori (H. pylori)-induced chronic atrophic gastritis (CAG) is a significant health concern. The role of microsomal triglyceride transfer protein (MTTP) in CAG progression has not been explored, presenting a critical knowledge gap in understanding H. pylori-induced CAG pathogenesis. Sprague-Dawley rats and gastric epithelial cell line were infected with H. pylori to build CAG model. The mRNA and protein levels of DNA methyltransferase 1 (DNMT1), MTTP, and glutathione peroxidase 4 (GPX4) were measured by quantitative real-time PCR (RT-qPCR) and western blotting, respectively. Moreover, the localization of DNMT1 and MTTP was detected via immunohistochemistry. Furthermore, the pathological changes of gastric tissue were analyzed by HE staining. The MTTP expression was downregulated in CAG. Moreover, overexpression of MTTP in gastric epithelial cells could suppress the inflammatory response induced by H. pylori infection and ferroptosis by upregulating GPX4 expression. In addition, DNMT1 expression was upregulated in CAG and was negatively correlated with MTTP expression. Furthermore, DNMT1 could target MTTP promoter to activate methylation and downregulate MTTP expression. DNMT1 downregulated the MTTP expression through methylation, and thus mediate inflammasome-ferroptosis processes via GPX4 in the H. pylori-induced CAG. Chronic atrophic gastritis (CAG) is a condition where the stomach lining becomes thinner and more damaged over time. It is often caused by infection with common stomach bacteria called Helicobacter pylori (H. pylori). CAG increases the risk of developing stomach cancer, so understanding how it develops is important for finding better treatments. In this study, we looked at a protein called MTTP, which usually helps with fat transport in cells. We found that MTTP levels are much lower in the stomachs of people and animals with CAG. When we increased MTTP levels in stomach cells in the lab, the cells were less damaged by H. pylori. This means MTTP may help protect stomach cells. We also discovered that another protein, DNMT1, plays a role in reducing MTTP levels. DNMT1 can “turn off” genes using a process called DNA methylation. When DNMT1 levels were high, MTTP levels went down. But when we blocked DNMT1 in animals, MTTP levels stayed higher and stomach damage was reduced. These findings suggest that boosting MTTP or blocking DNMT1 might be a new way to help prevent or treat stomach problems caused by H. pylori.