ZC3H13-mediated the m6A modification of PAX9 suppresses the progression of reflux esophagitis via improving esophageal epithelial barrier dysfunction.

The role of N6-methyladenosine (m6A) in reflux esophagitis (RE) has not been fully elucidated. We performed MeRIP-seq to profile m6A-modified genes in RE. The expression of ZC3H13 and PAX9 was analyzed in non-RE and RE tissues using RT-qPCR and western blot, followed by functional assays in human esophageal epithelial cells (HEEC). PAX9, an m6A-modified gene, was m6A-modified and downregulated in RE samples. Furthermore, ZC3H13, an m6A writer, was notably downregulated in RE samples. Overexpression of ZC3H13 strongly elevated the m6A modification, stability and expression levels of PAX9 in HEEC cells. Additionally, both PAX9 and ZC3H13 overexpression significantly suppressed the inflammatory response and oxidative stress, as well as improved epithelial barrier dysfunction and inhibited epithelial mesenchymal transition in HCl-treated HEEC cells. Notably, the anti-inflammatory, antioxidant stress and endothelial barrier protective roles of ZC3H13 were abolished by PAX9 deficiency. Collectively, ZC3H13 mitigates RE progression through upregulating PAX9.