YAP drives Helicobacter pylori–induced metaplastic changes in gastric epithelium

BACKGROUND & AIMS: Helicobacter pylori infection triggers a spectrum of metaplastic changes in the gastric epithelium; however, the upstream regulatory mechanisms remain unclear. In human gastric epithelial models, H. pylori CagA-dependent signaling stabilized and activated YAP, thereby promoting metaplastic reprogramming of the gastric epithelium. METHODS: Human gastric tissue specimens were obtained from patients at Severance Hospital, Yonsei University College of Medicine. Human gastric epithelial cell lines (AGS, MKN74, N87, KATO III) and 8- to 10-week-old C57BL/6J mice were used. Transcriptomic analysis, immunoprecipitation, histologic and immunofluorescence staining, and molecular assays (western blotting and qRT-PCR) were performed to assess YAP signaling and metaplastic marker expression. RESULTS: Genetic and pharmacologic modulation of YAP and OTUB2 demonstrated that these metaplastic marker alterations are YAP-dependent. In vivo, comparative infection with H. pylori with or without CagA revealed significantly increased spasmolytic polypeptide-expressing metaplasia markers from chief cells (GSII/GIF, CD44v9), parietal cell loss, and an expanded proliferative region in the presence of CagA. H. felis infection was used to broaden the dynamic range of in vivo pathological outcomes. Manipulating YAP specifically in chief cells with a Mist1 driver verified both the induction and suppression of these lesions, and the administration of recombinant OTUB2 and treatment with selective inhibitors enhanced and reduced metaplastic signaling, respectively. CONCLUSIONS: YAP acts as a central regulator of H. pylori-induced metaplastic transformation by reprogramming gastric epithelial and chief cell lineages. OTUB2 serves as an upstream modulator that reinforces YAP stability and signaling, highlighting YAP as a potential therapeutic target for preventing metaplastic progression.