Isoquercitrin Inhibits Laryngopharyngeal Reflux Disease-Related Pharyngeal EMT by Regulating the ASIC3/RhoA/β-Catenin Positive Feedback Signaling Pathway.

Authors

Qi Wang, Shuangning Song, Xiuxian Wei, Zhengwen Piao, Hai Li

Published in

Journal of gastroenterology and hepatology. Sep 30, 2026. Epub Sep 30, 2026.

Abstract

Laryngopharyngeal reflux disease (LPRD) lacks effective targeted treatments, as conventional proton pump inhibitors cannot alleviate bile acid-induced mucosal damage and epithelial-mesenchymal transition (EMT). This study aimed to explore the mechanism of acidic bile-mediated LPRD progression and the therapeutic potential of isoquercitrin. An acidic bile-stimulated HHPC cell model and a pyloric ligation-induced rat LPRD model were established. High-throughput screening was used to identify optimal active monomers. Multiple molecular biological assays, molecular docking, microscale thermophoresis, and luciferase reporter assays were performed to verify protein binding and signaling regulation. Gradient-dose isoquercitrin treatment was applied for in vitro and in vivo validation. Pathologically, acidic bile (pH 4.0) disrupted pharyngeal epithelial barrier integrity, decreased E-cadherin expression, and induced EMT by activating the ASIC3/RhoA/β-catenin positive feedback loop, in which β-catenin/TCF/LEF further transcriptionally upregulated ASIC3. High-throughput screening confirmed isoquercitrin (IC50 = 34.2 μM) as the optimal anti-EMT monomer. Mechanistically, isoquercitrin directly bound the N426/S425 sites of β-catenin, restrained β-catenin nuclear translocation, and thereby blocked the positive feedback cascade, restored epithelial barrier homeostasis, and reversed bile-induced EMT. Consistently, in vivo LPRD models verified that isoquercitrin dose-dependently attenuated inflammatory infiltration, rescued pharyngeal tissue structural damage, downregulated ASIC3, and recovered E-cadherin expression. In conclusion, isoquercitrin ameliorates LPRD by inhibiting EMT via targeting the ASIC3/RhoA/β-catenin feedback pathway. These findings identify isoquercitrin as a novel therapeutic candidate for LPRD.

PMID:
42815886
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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