Metformin attenuates coal dust nanoparticle-induced pulmonary fibrosis by modulating inflammation and...

Coal worker pneumoconiosis is an occupational pulmonary fibrosis (PF) caused by prolonged exposure to respirable coal dust (CD), with limited therapeutic options. Here, we explored the antifibrotic effects of metformin (Met) in CD-nanoparticle (CD-NP)-induced PF, focusing on its preventive and therapeutic potential. In vivo, Met was administered at different doses (low: 31.25 mg/kg; high: 62.5 mg/kg) and timings (preventive: starting on day 2; therapeutic: starting on day 22) during CD-NP-induced PF in mice. Assessments included body weight monitoring, lung coefficient calculation, histopathological analysis, and quantification of inflammatory factors and fibrotic markers. In vitro, BEAS-2B and A549 cells were treated with CD-NPs ± Met (1 mM), followed by analyses of cell proliferation, migration/invasion, and epithelial-mesenchymal transition (EMT) and expression of fibrotic proteins. Additionally, pathological signal changes were analyzed by immunohistochemical staining, Western blotting, reactive oxygen species fluorescence probes, and immunofluorescence staining. The results showed that Met significantly alleviated CD-NP-induced pathological changes, including body weight loss; increased the lung coefficient; lung morphological damage; inflammatory cell infiltration; collagen deposition; and the upregulation of pro-EMT/fibrotic proteins (e.g., α-smooth muscle actin and collagen type 1). Notably, preventive administration of low-dose Met had the most pronounced effects. In vitro, Met inhibited CD-NP-induced cell hyperproliferation, migration, invasion, and abnormal EMT/fibrotic protein expression. Mechanistically, Met suppressed CD-NP-triggered abnormal activation of pathological signaling, including oxidative stress, insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R), protein kinase B (AKT)/glycogen synthase kinase (GSK)3β, nuclear factor (NF)-κB/nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) signaling. These findings indicate that Met attenuates CD-NP-induced PF by inhibiting oxidative stress, inflammation, and EMT, potentially by targeting IGF1/IGF1R, AKT/GSK3β, and NF-κB/NLRP3 signaling. Its preventive efficacy highlights promising translational value for occupational PF intervention.