7,8‐Dihydroxyflavone Suppresses Experimental Pulmonary Fibrosis by Inhibiting Fibroblast‐to‐Myofibroblast Transformation and Epithelial–Mesenchymal Transition

Pulmonary fibrosis (PF) is a chronic and progressive fibrotic disease with limited treatment options, which highlights the urgent need for novel therapeutic strategies. Fibroblast-to-myofibroblast transformation (FMT) and epithelial-mesenchymal transition (EMT) are central mechanisms driving fibrosis progression. This study investigated the therapeutic potential and mechanisms of 7,8-dihydroxyflavone (7,8-DHF), a selective tropomyosin receptor kinase B (TrkB) agonist, in experimental PF models in vitro and in vivo. Human lung fibroblast cells (MRC-5) and mouse lung epithelial cells (MLE-12) were stimulated with transforming growth factor-β1 (TGF-β1). 7,8-DHF suppressed the migration, proliferation and differentiation of TGF-β1-induced MRC-5 cells as well as reduced the protein levels of fibrotic markers including α-smooth muscle actin, connective tissue growth factor, collagen I and fibronectin. Moreover, 7,8-DHF attenuated the migration and EMT of TGF-β1-induced MLE-12 cells. Additionally, 7,8-DHF alleviated bleomycin-induced PF in mice. Mechanistically, 7,8-DHF inhibited the TGF-β1/Smad2/3 signalling pathway in both models. Notably, the anti-fibrotic effects were not reversed by the selective TrkB inhibitor ANA-12, suggesting TrkB-independent action. Instead, 7,8-DHF suppressed Akt activity in MRC-5 and MLE-12 cells. These findings demonstrate that 7,8-DHF alleviates PF by targeting FMT and EMT via TGF-β1/Smad2/3 signalling and Akt inhibition. These results highlight 7,8-DHF as a promising therapeutic candidate for PF.