Estrogen-related receptor-gamma influences Helicobacter pylori infection by regulating TFF1 in gastric cancer

Helicobacter pylori infection is a crucial factor in the development of gastric cancer (GC). Molecular therapeutic targets and mechanisms contributing to H. pylori infection-associated GC induction are poorly understood and this study aimed to fill that research gap. We found that the nuclear receptor estrogen-related receptor gamma (ESRRG) is a candidate factor influencing H. pylori infection-driven GC. ESRRG suppressed H. pylori infection and cell growth induced by H. pylori infection in GC cells and organoid models In addition, H. pylori infection downregulates ESRRG expression. Gene expression profiling revealed that trefoil factor 1 (TFF1), a well-known tumor suppressor in GC, is a downstream target of ESRRG. Mechanistically, ESRRG directly binds to the TFF1 promoter and induces TFF1 gene expression. Furthermore, TFF1 activation by ESRRG was inhibited by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/p65, which is induced by inflammation, such as by H. pylori infection. Our current study provides new molecular insights into how ESRRG regulates H. pylori infection, contributing to GC development. We suggest that modulation of ESRRG-suppressing H. pylori infection could be a therapeutic target for the treatment of GC patients.