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

ABSTRACT 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.