Lidocaine alleviates pulmonary fibrosis by attenuating fibroblast activation and restoring lung microbiome-metabolome homeostasis

Pulmonary fibrosis is a devastating disease with limited treatment options. Lidocaine, a local anesthetic, has demonstrated anti-inflammatory and anti-tumor properties, but its therapeutic potential and mechanisms in pulmonary fibrosis remain largely unexplored. In this study, lidocaine administration significantly attenuated bleomycin (BLM)-induced lung injury and fibrosis. Lidocaine suppressed TGF-β1-induced human lung fibroblast differentiation, proliferation, and migration. Mechanistically, lidocaine inhibited the activation and differentiation of fibroblasts to myofibroblasts by blocking the MAPK signaling pathway. Crucially, lidocaine reversed BLM-induced lung microbiota dysbiosis and concurrently restored host metabolic changes, particularly amino acid metabolism. Integrated microbiome–metabolome analysis revealed significant correlations between lidocaine-altered bacterial genera and key amino acid metabolites, suggesting that lidocaine disrupts pathogenic bacteria–metabolite axes that drive fibrosis progression. In conclusion, our study demonstrated that lidocaine ameliorates pulmonary fibrosis by inhibiting MAPK-mediated fibroblast activation, and restoring lung microenvironment homeostasis by modulating the microbiota composition and host metabolic reprogramming. These findings position lidocaine as a novel multitarget therapeutic candidate for pulmonary fibrosis.