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Background: Recent studies have shown that gastrokine 1 (GKN1), an important tumor suppressor gene, is downregulated in Helicobacter pylori (H. pylori) infected gastric mucosa and gastric cancer. However, the underlying mechanism is poorly understood. Herein, we investigated the potential mechanism of H. pylori‐induced GKN1 downregulation. Materials and methods: GKN1 and AU‐rich element RNA‐binding factor 1 (AUF1) expressions were assessed by quantitative real‐time PCR, Western blot, or immunohistochemistry in H. pylori‐infected tissues and H. pylori co‐cultured cell lines. The regulation of AUF1 on GKN1 was determined by RNA pulldown assay, RNA immunoprecipitation, mRNA turnover, and luciferase activity assays. The involvement of phosphorylated extra‐cellular signal‐regulated kinase (p‐ERK) or CagA in H. pylori‐induced AUF1 expression was verified using p‐ERK inhibitor or CagA knockout H. pylori. In addition, the cell proliferation and migration capacities of AUF1‐knockdown cells were investigated. Results: GKN1 expression progressively decreased from H. pylori‐infected gastritis to gastric cancer tissues. H. pylori co‐culture also induced significant GKN1 reduction in GES‐1 and BGC‐823 cells. Besides, the mRNA level of GKN1 and AUF1 in human gastric mucosa showed negative correlation significantly. AUF1 knockdown resulted in upregulation of GKN1 expression and promoted GKN1 mRNA decay by binding the 3′ untranslated region of GKN1 mRNA H. pylori‐induced AUF1 expression was associated with p‐ERK activation and CagA. Furthermore, knockdown of AUF1 significantly inhibited cell viability, migration ability, and arrested fewer cells in S‐phase. Conclusion: Our data demonstrated that H. pylori infection downregulated GKN1 expression via the CagA/p‐ERK/AUF1 pathway. AUF1 promoted gastric cancer at least partly through downregulating GKN1, which presented a novel potential target for the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]