The Serotonergic and Cholinergic Signaling Pathways Drive Gastric Precancerous Lesions and Its Potential Mechanism.

Authors

Shengli Gao, Xufei Feng, Nana Zhang, Jia Su, Yuyan Wang, Linghan Kong, Jianing Zhou, Hui Dong, Feifei Guo

Published in

Cancer science. Oct 17, 2026. Epub Oct 17, 2026.

Abstract

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-clamp recording, immunofluorescence, and chemogenetics to investigate serotonergic and cholinergic signaling in GPL. An N-methyl-N-nitrosourea (MNU) -induced mouse model was used for in vivo validation. High 5-HTR1D 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-HT evoked non-selective cation currents involving 5-HTR1D and TRPV4 in gastric epithelial and cancer cells, as supported by both pharmacological inhibition and siRNA-mediated TRPV4 knockdown. Blockade of 5-HTR1D or TRPV4 attenuated intestinal metaplasia and dysplasia, and this improvement was accompanied by reduced AKT/mTOR activation in GPL mice. Increased gastric M3R/5-HT co-localization 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-HT levels and alleviated gastric pathology in GPL mice. These findings suggest that 5-HT/5-HTR1D signaling may promote TRPV4-involved 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-HT secretion and thereby potentially contribute to GPL progression. This work establishes a novel neuro-epithelial network linking vagal cholinergic output to serotonergic signaling that may be involved in GPL progression, providing potential targets for prevention and intervention.

PMID:
42888890
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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