Zanubrutinib mitigates pulmonary fibrosis in aged mice by targeting the Wnt/β-catenin signaling pathway

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by a poor survival prognosis of only 3-5 years post-diagnosis and limited treatment options. Notably, the incidence of IPF is particularly high among the elderly population. Zanubrutinib is a second-generation Bruton's tyrosine kinase (BTK) inhibitor independently developed by BeOne Medicines Ltd, which is approved by the FDA for a variety of B-cell lymphomas, including mantle-cell lymphoma. In this study, we discuss the potential effects and mechanisms of Zanubrutinib on aging lung fibrosis in vivo and in vitro. In vivo studies demonstrated that Zanubrutinib could effectively alleviate bleomycin-induced pulmonary fibrosis in senescent mice and significantly reduce the expression of fibrosis markers and senescence markers. In vivo studies demonstrated that Zanubrutinib inhibited the fibrotic phenotype as well as the senescent phenotype of mouse fibroblasts and mouse epithelial cells. Zanubrutinib effectively inhibited BTK phosphorylation and Wnt/β-catenin signaling pathway transduction, and reduced β-catenin entry into the nucleus. In conclusion, Zanubrutinib may alleviate the senescence-associated phenotype and mitigate senescence-associated pulmonary fibrosis by inhibiting the Wnt/β-catenin signaling pathway.