Antifibrotic Efficacy of Daclatasvir Against Pulmonary Fibrosis: Insights From Network Pharmacology, Molecular Docking, Dynamics, and Preclinical Evaluations

Daclatasvir (DAC), a direct-acting antiviral agent approved for hepatitis C virus (HCV) infection, has shown antifibrotic potential in animal models. However, its therapeutic effect in pulmonary fibrosis (PF) remains to be fully elucidated. The present study evaluated DAC in a bleomycin (BLM)-induced PF rat model, integrating network pharmacology, molecular docking, and molecular dynamics (MD) simulation to decipher its mechanisms. Target prediction and enrichment analysis identified fibrosis-relevant proteins, including histone deacetylase (HDAC)1, HDAC2, NFκB1, mTOR, HIF1A, and MMPs. KEGG and STRING-based analyses indicated DAC's involvement in inflammatory, epigenetic, and profibrotic pathways. Docking studies confirmed stable interactions between DAC and HDAC isoforms, which were further validated by 100 ns MD simulations using GROMACS. PCA analyses also confirmed complex stability, comparable to known inhibitors vorinostat and mocetinostat. In vivo, DAC at 6.2 mg/kg/day (clinically equivalent dose) significantly attenuated BLM-induced lung injury by reducing inflammatory cell infiltration, oxidative stress, and collagen accumulation. Histopathological assessments showed marked preservation of lung microarchitecture. Interestingly, a higher dose (12.4 mg/kg/day) showed reduced efficacy and increased lung index, indicating dose sensitivity. These findings suggest that DAC possesses dose-dependent antifibrotic activity in PF and warrants further exploration as a repurposable therapeutic candidate.