Background <p>Silicosis is a severe and globally prevalent lung disease characterized by progressive pulmonary fibrosis. Recent studies suggested that N⁶-methyladenosine (m⁶A) modification is implicated in the pathogenesis of lung diseases. However, the function role of m⁶A modification in silicosis is still mostly unknown.</p> Methods <p>Silica-exposed bronchial epithelial cell model and silicosis mice model were established to determine the role of m⁶A modification in silica-induced pulmonary fibrosis. Then, a series of experimental methods including dot blot, immunofluorescence, RIP assay, were performed to explore the underlying mechanisms of methyltransferase-like 3 (METTL3)-mediated Differentiated embryo-ehon-drocyte expressed gene1 (DEC1) m⁶A modification in epithelial-mesenchymal transition (EMT) process and pulmonary fibrosis. Finally, we used small interfering RNAs (siRNAs) and AAV6 vectors targeting METTL3 to investigate the effect of METTL3 in silica-induced pulmonary fibrosis.</p> Results <p>We found that silica-induced EMT process was accompanied by the increased expression of DEC1. Mechanistically, DEC1 was identified as the downstream effector of METTL3. METTL3 directly recognized and bound to the m⁶A site on DEC1 mRNA, regulated DEC1 mRNA stability, leading to its post-transcriptional activation. DEC1 then activated PI3K/Akt signaling pathway, and played a critical role in silica-induced pulmonary fibrosis by promoting inflammation and EMT process. In particular, the EMT process and silica-induced pulmonary fibrosis were alleviated by siRNAs and AAV6 vectors targeting METTL3 in vitro and in vivo, respectively.</p> Conclusions <p>The m⁶A-mediated regulation of DEC1 overexpression may underlie the pathogenesis of silicosis, suggesting that modulation of METTL3 mediated DEC1 expression represents a promising prevention target.</p>