Work

M6A-methylated MUC1 drives silica-induced lung inflammation and fibrosis

Year: 2025

Type: article

Abstract: Silicosis is a chronic and progressive lung disease induced by long-term environmental silica inhalation, characterized by sustained inflammation and progressive fibrosis. This study aimed to investigate the role of N 6 -methyladenosine (m 6 A)-modified mucin 1 (MUC1) in silica-induced pulmonary inflammation and fibrosis. Here, clinical analyses revealed significant upregulation of MUC1 expression and m 6 A modification levels in blood samples from silicosis patients. Single-cell RNA sequencing and in vivo experiments confirmed that MUC1 overexpression was predominantly localized to lung epithelial cells following silica exposure. In vitro , silica particles induced inflammation and epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, accompanied by elevated total m 6 A levels and MUC1 expression. Mechanistically, chromatin immunoprecipitation assays showed that CBP-mediated H3K27 acetylation facilitated the transcriptional activation of m 6 A methyltransferase METTL3, which enhanced m 6 A modification of MUC1 mRNA, promoting its stability and expression via YTHDF2 recognition. Functional assays demonstrated that MUC1 activated NF-κB/ZEB1 and β-catenin/Snail signaling pathways, thereby promoting inflammation and collagen deposition. Silencing MUC1 effectively suppressed these pathogenic processes. In vivo , targeting m 6 A modification significantly alleviated lung inflammation and fibrosis through inhibiting EMT progression. Collectively, this study identifies aberrant m 6 A modification of MUC1 as a critical driver of silica-induced lung inflammation and fibrosis and highlights m 6 A-regulated MUC1 as a promising intervention target for silicosis.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.119576