Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. So far, the only drugs approved for the treatment of IPF are Nintedanib and Pirfenidone. Zanubrutinib, a BTK small molecule inhibitor, is approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro.
Methods: In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indexes were evaluated. The in vitro experiments were used a TGF-β1-treated fibroblast model to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and explored the underlying signaling pathways mechanism.
Results: In vivo experiments proved that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro mechanism study indicated that zanubrutinib could suppress collagen deposition, myofibroblast activation by inhibiting the TGF-β1/Smad pathway and induce autophagy through the TGF-β1/mTOR pathway.
Conclusions: Zanubrutinib could alleviate bleomycin- induced lung fibrosis in mice by inhibiting the TGF-β1 signaling pathway.