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

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 N⁶-methyladenosine (m⁶A)-modified mucin 1 (MUC1) in silica-induced pulmonary inflammation and fibrosis. Here, clinical analyses revealed significant upregulation of MUC1 expression and m⁶A 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 m⁶A levels and MUC1 expression. Mechanistically, chromatin immunoprecipitation assays showed that CBP-mediated H3K27 acetylation facilitated the transcriptional activation of m⁶A methyltransferase METTL3, which enhanced m⁶A 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 m⁶A modification significantly alleviated lung inflammation and fibrosis through inhibiting EMT progression. Collectively, this study identifies aberrant m⁶A modification of MUC1 as a critical driver of silica-induced lung inflammation and fibrosis and highlights m⁶A-regulated MUC1 as a promising intervention target for silicosis.