Deciphering the multi-organ anti-fibrotic mechanisms of pirfenidone and nintedanib via network pharmacology.

Abstract

Background: Fibrosis is a systemic disorder driven by inflammation, immune imbalance, and extracellular matrix remodeling. Pirfenidone (PFD) and nintedanib (NTB), approved for idiopathic pulmonary fibrosis, may exert broader antifibrotic effects by modulating conserved fibrotic signaling pathways across multiple organs, including the heart, pancreas, lungs, liver, skin, intestine, bone marrow, eyes, and kidneys.

Methods: Organ-specific fibrosis-related genes were retrieved from GeneCards, while drug-target data for PFD and NTB were collected from CTD, STITCH, KEGG, BindingDB, and TargetNet. Overlapping targets were subjected to pathway enrichment analysis using KEGG, Reactome, and WikiPathways.

Results: 72 protein targets for PFD and 27 for NTB were identified after removal of duplicate targets. PFD showed common targets with cardiac-20, pancreatic-24, lung-38, liver-34, skin-29, intestine-23, bone marrow-43, eyes-18, and kidney fibrosis-30, while NTB showed 2, 6, 13, 6, 8, 5, 16, 4, and 3 targets, respectively. PFD regulates immune and fibrotic pathways beyond the lung (IL-17, TNF, HIF-1, TGF-β, and matrix metalloproteinase activation), which are relevant to hepatic, renal, and hematopoietic fibrosis. NTB modulated PI3K-Akt, MAPK, and Ras signaling in bone marrow, skin, and intestinal fibrosis.

Conclusions: These findings suggest that PFD and NTB target key molecular pathways involved in multi-organ fibrosis, supporting their repurposing for fibrotic diseases beyond the lung.