OBJECTIVE: Neutrophil extracellular traps (NETs) play crucial roles in idiopathic inflammatory myositis-associated interstitial lung disease (IIM-ILD) pathogenesis. The involvement and mechanism of alveolar epithelial cells in the pathogenesis of IIM-ILD remain unclear. This study aimed to clarify the hypothesis that NETs promote alveolar epithelial-mesenchymal transition (EMT), which contributes to IIM-ILD. METHODS: Lung biopsy puncture tissue from three IIM-ILD patients was used for pathological analysis. An experimental mouse model of autoimmune myositis with ILD (EAM-ILD) was used for mechanism validation in vivo. A549 cells were treated with NETs and assessed using Western blotting, immunofluorescence, and RNA sequencing techniques. STING inhibitors were employed to assess the efficacy of stimulator of interferon gene (STING) as a therapeutic target for EAM-ILD. RESULT: There was a marked EMT and the activation of cGAS-STING pathway found in the lung samples of IIM-ILD patients (N = 3) and in A549 cells in vitro (P <
0.05). RNA sequencing indicates that NETs induce an upregulation of inflammation and fibrosis-related pathways in A549 cells, with high expression of the STING-related pathway. The STING inhibitor can prevent EMT in alveolar epithelial cells both in vivo and in vitro, and reduce the inflammatory response in the lung tissue of the EAM-ILD mouse (P <
0.05). CONCLUSION: These in vitro and ex vivo experiments demonstrate that NETs promote EAM-ILD by inducing EMT in alveolar epithelial cells and that the cGAS-STING signaling pathway is one of the potential mechanisms of action. Targeting STING is a potential therapeutic strategy for treating IIM-ILD.