{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T07:41:10Z","timestamp":1792222870043,"version":"4.4.0"},"reference-count":73,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:00:00Z","timestamp":1792195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:00:00Z","timestamp":1792195200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2025MS458"],"award-info":[{"award-number":["ZR2025MS458"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Gastric cancer (GC) is a leading lethal malignancy globally. Gastric precancerous lesion (GPL) represents a critical step in GC, but its neural regulatory mechanisms remain largely unclear. We combined bioinformatics, patch\u2010clamp recording, immunofluorescence, and chemogenetics to investigate serotonergic and cholinergic signaling in GPL. An N\u2010methyl\u2010N\u2010nitrosourea (MNU) \u2010induced mouse model was used for in\u00a0vivo validation. High 5\u2010HTR1D expression correlated with poor survival in gastric adenocarcinoma patients and was upregulated in AGS and MKN45 cells, as well as in gastric tissues of GPL mice. 5\u2010HT evoked non\u2010selective cation currents involving 5\u2010HTR1D and TRPV4 in gastric epithelial and cancer cells, as supported by both pharmacological inhibition and siRNA\u2010mediated\n                    <jats:italic>TRPV4<\/jats:italic>\n                    knockdown. Blockade of 5\u2010HTR1D or TRPV4 attenuated intestinal metaplasia and dysplasia, and this improvement was accompanied by reduced AKT\/mTOR activation in GPL mice. Increased gastric M3R\/5\u2010HT co\u2010localization was associated with elevated acetylcholine and overactivated cholinergic neurons in the dorsal motor nucleus of the vagus (DMV). Chemogenetic inhibition of DMV cholinergic neurons decreased ChAT and 5\u2010HT levels and alleviated gastric pathology in GPL mice. These findings suggest that 5\u2010HT\/5\u2010HTR1D signaling may promote TRPV4\u2010involved cation currents, contributing to mucosal pathology and intestinal metaplasia in GPL model mice, whereas DMV cholinergic neurons projecting to the stomach may facilitate gastric 5\u2010HT secretion and thereby potentially contribute to GPL progression. This work establishes a novel neuro\u2010epithelial network linking vagal cholinergic output to serotonergic signaling that may be involved in GPL progression, providing potential targets for prevention and intervention.\n                  <\/jats:p>","DOI":"10.1111\/cas.70563","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T07:00:46Z","timestamp":1792220446000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Serotonergic and Cholinergic Signaling Pathways Drive Gastric Precancerous Lesions and Its Potential Mechanism"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2692-2946","authenticated-orcid":false,"given":"Shengli","family":"Gao","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Qingdao University  Qingdao Shandong 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