Tryptanthrin alleviate lung fibrosis via suppression of MAPK/NF-κB and TGF-β1/SMAD signaling pathways in vitro and in vivo

Idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown etiology, remains a therapeutic challenge with limited treatment options. This study investigates the therapeutic potential and molecular mechanisms of Tryptanthrin, a bioactive indole quinazoline alkaloid derived from Isatis tinctoria L., in pulmonary fibrosis. In a bleomycin-induced murine IPF model, Tryptanthrin administration (5 and 10 mg/kg/ day for 28 days) significantly improved pulmonary function parameters and attenuated histological evidence of fibrosis. Mechanistic analysis revealed dual pathway modulation: Tryptanthrin suppressed MAPK/NF-kappa B signaling through inhibition of phosphorylation events, subsequently reducing pulmonary levels of proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6). Concurrently, it attenuated TGF-beta 1/Smad pathway activation by decreasing TGF-beta 1 expression and Smad2/3 phosphorylation, thereby downregulating fibrotic markers including COL1A1, alpha-smooth muscle actin (alpha-SMA), and fibronectin in lung tissues. Complementary in vitro studies using Lipopolysaccharide (LPS) or TGF-beta 1-stimulated NIH3T3 fibroblasts confirmed these anti-inflammatory and antifibrotic effects through analogous pathway inhibition. Our findings demonstrate that Tryptanthrin exerts therapeutic effects against pulmonary fibrosis via coordinated modulation of both inflammatory (MAPK/NF-kappa B) and fibrotic (TGF-beta 1/Smad) signaling cascades, suggesting its potential as a novel multi-target therapeutic agent for IPF management.