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However, the underlying mechanism remains largely unclear. In this study, we uncover an essential role of Hp. infection in mediating tumor suppressor gene silencing in gastric epithelial cells through promoter DNA hypermethylation. Hepatocyte nuclear factor HNF4A was downregulated in GC and predicted poor survival. The in vitro and in vivo assays together confirmed that HNF4A plays a tumor suppressive role in GC. Single-cell analysis showed that HNF4A was selectively expressed in gastric epithelial cells. Besides, the reduced HNF4A expression in GC was due to promoter DNA hypermethylation. More importantly, we have provided strong evidence that Hp. infection causes HNF4A down-regulation by hypermethylation of its gene promoter. Meanwhile, silencing of HNF4A resulted in loss of epithelial polarity and activation of TGF\u03b2-induced EMT signaling in gastric epithelial cells by transcriptionally regulating the expression of downstream target genes. In addition, the rescue assays indicated that Hp. infection activated EMT signaling of gastric epithelial cells in a HNF4A-dependent manner, thereby driving gastric tumorigenesis and metastasis. In conclusion, HNF4A is a tumor suppressor gene in GC. Hp. infection causes silence of the HNF4A gene by hypermethylation of its promoter, which then disrupts epithelial polarity and induces EMT signaling in gastric epithelial cells, thereby driving gastric tumorigenesis and metastasis.<\/jats:p>","DOI":"10.1038\/s41419-025-08029-6","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T06:33:37Z","timestamp":1759732417000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Hypermethylation-mediated HNF4A silencing by Helicobacter pylori infection drives gastric cancer by disrupting epithelial cell polarity and activating EMT signaling"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-8867","authenticated-orcid":false,"given":"Dandan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiwei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lantian","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyun","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0639-1466","authenticated-orcid":false,"given":"Weidong","family":"Leng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8527-5278","authenticated-orcid":false,"given":"Shanshan","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"8029_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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