Integrated in silico and experimental validation reveals the comparative efficacy of repurposable statins for the treatment of idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease that currently has limited treatment options available. This study evaluated seven statins for their potential repurposing to treat IPF using network pharmacology (NP). Atorvastatin, pravastatin, rosuvastatin, and simvastatin were identified as having favourable multi-target interaction profiles against IPF-related proteins and were further analysed for their interactions with HDAC1 and HDAC2 using molecular docking and dynamics studies. To confirm these predictions, the antifibrotic efficacy of these 4 selected statins, at equimolar doses, was compared in the experimental model of bleomycin (BLM)-induced IPF in rats. Following this comparative analysis, atorvastatin was chosen for detailed molecular evaluation, which was performed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting techniques. NP revealed that atorvastatin, pravastatin, rosuvastatin, and simvastatin have higher edge scores in the network. Rosuvastatin and atorvastatin had binding affinities for HDAC1 and HDAC2 comparable to their known ligands, mocetinostat and vorinostat, respectively. In the BLM-induced IPF model, atorvastatin, rosuvastatin, pravastatin, and simvastatin effectively prevented collagen accumulation in the lungs, reduced the lung index, and improved tissue architecture. Atorvastatin significantly reduced lung index ( p < 0.001) and hydroxyproline content ( p < 0.05) compared with the BLM group, while pravastatin also significantly reduced hydroxyproline content ( p < 0.05). Rosuvastatin and simvastatin showed non-significant reductions in hydroxyproline content. Furthermore, molecular analysis revealed that atorvastatin lowered HDAC2 mRNA expression ( p < 0.05) and decreased both mRNA and protein levels of TGF-β1 ( p < 0.05) and α-SMA ( p < 0.05). The findings clearly identify atorvastatin, and to a lesser extent rosuvastatin, pravastatin, and simvastatin as frontrunners for repurposing in the treatment of IPF. This suggests a novel potential mechanism involving HDAC modulation.