Downregulation of MUC6 improves esophageal epithelial barrier dysfunction and inhibits epithelial-mesenchymal transition in reflux esophagitis.

BACKGROUND: Reflux esophagitis (RE) is a chronic inflammatory condition resulting from the reflux of gastric contents. Mucin 6 (MUC6), a member of the mucin family, has been found to have dysregulated expression in various esophageal diseases. However, the specific role of MUC6 in RE remains largely unclear. METHODS: MUC6 levels were detected in esophageal tissues between RE patients and non-RE patients using RT-qPCR and western blot assays. Additionally, to stimulate RE in vitro, human esophageal epithelial cells (HEEC) were exposed to hydrochloric acid (HCl) with a pH of 3.0. To mimic RE in vivo, hemipyloric ligation combined with cardiomyotomy was performed. RESULTS: MUC6 levels were significantly higher in esophageal tissues of RE patients compared to non-RE patients. Meanwhile, elevated MUC6 levels were also observed in HCl-stimulated HEEC cells and in esophageal tissues of rats with RE. Downregulation of MUC6 notably attenuated the inflammatory response both in vitro and in vivo, as evidenced by a reduced production of IL-6. Additionally, silencing MUC6 remarkably improved esophageal epithelial barrier dysfunction in vitro and in vivo through upregulating tight junction protein ZO-1. Meanwhile, MUC6 knockdown resulted in increased levels of E-cadherin, and decreased levels of N-cadherin, vimentin, transforming growth factor-beta 1 (TGF-β1) and Smad3 in RE models both in vitro and in vivo. CONCLUSION: Collectively, MUC6 knockdown could improve esophageal epithelial barrier dysfunction and inhibit epithelial-mesenchymal transition in HCl-stimulated HEEC cells and in esophageal tissues of RE rats, potentially via modulation of the TGF-β1/Smad3 signaling pathway. These data suggested that MUC6 may be a promising target for diagnosis and treatment of RE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12876-025-04336-6.