BACKGROUND: Helicobacter pylori (H. pylori) infection contributes significantly to gastric cancer (GC) progression. The intrinsic mechanisms of H. pylori-host interactions and their role in promoting GC progression need further investigation. In this study, we explored the potential role of fat mass and obesity-associated protein (FTO) in mediating Cytotoxin-associated gene A (CagA)-induced GC progression. METHODS: The effects of H. pylori infection on N RESULTS: Infection with cagA-positive H. pylori upregulated the expression of FTO, which was essential for CagA-mediated GC metastasis and significantly associated with a poor prognosis in GC patients. Mechanistically, CagA delivered by H. pylori enhanced FTO transcription via Jun proto-oncogene. Elevated FTO induced demethylation of m CONCLUSION: Our study revealed that FTO mediates the "hit-and-run" mechanism of CagA-induced GC progression, which suggests that the therapeutic targeting of FTO could offer a promising approach to the prevention of CagA-induced cancer progression.