Exosomal CagA induces macrophage polarization and ferroptosis by JAK1-2/STAT1 signaling pathway in Helicobacter pylori-associated gastritis

Helicobacter pylori ( H. pylori ) infection is a major cause of gastric diseases, with the virulence factor CagA carried by exosomes playing a crucial role in regulating inflammation. Ferroptosis and M1 polarization are key mechanisms in promoting inflammation, yet the role of CagA in inducing macrophage ferroptosis and M1 polarization to exacerbate gastric mucosal inflammation remains unclear.In this study, CagA-positive (CagA+) and CagA-negative (CagA-) H. pylori strains were co-cultured with gastric epithelial cells, and exosomes were isolated to assess their impact on macrophage polarization and ferroptosis markers. We found that exosomal CagA induces M1 polarization and ferroptosis in macrophages by activating the JAK/STAT1 signaling pathway. The ferroptosis inhibitor SLC7A11 plays a key role in CagA-induced ferroptosis. Furthermore, exosomal CagA enhances STAT1 nuclear expression, which binds to the SLC7A11 promoter, downregulating its expression. In biopsies from CagA + H. pylori -infected gastritis patients, increased iNOS levels and reduced SLC7A11 expression were observed. Our findings indicate that exosomal CagA promotes macrophage M1 polarization and ferroptosis through the JAK/STAT1 signaling pathway. This study provides new insights and potential therapeutic targets for H. pylori -associated gastritis. • Exosomal CagA derived from H. pylori -infected GES-1 cells is transferred into macrophages. • Exosomal CagA promotes M1 polarization and ferroptosis of macrophages. • Exosomal CagA activates the JAK/STAT1 signaling pathway to drive macrophage reprogramming. • STAT1 binds to the SLC7A11 promoter and represses its expression, facilitating ferroptosis. • Biopsies from H. pylori CagA + gastritis patients show increased iNOS and decreased SLC7A11 expression.