AUTHOR=Li Xiaohe , Liu Xiaowei , Deng Ruxia , Gao Shaoyan , Yu Haiyan , Huang Kai , Jiang Qiuyan , Liu Rui , Li Xiaoping , Zhang Liang , Zhou Honggang , Yang Cheng TITLE=Nintedanib Inhibits Wnt3a-Induced Myofibroblast Activation by Suppressing the Src/β-Catenin Pathway JOURNAL=Frontiers in Pharmacology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.00310 DOI=10.3389/fphar.2020.00310 ISSN=1663-9812 ABSTRACT=

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by epithelial cell damage, myofibroblast activation, and collagen deposition. Multiple studies have documented that the Wnt/β-catenin pathway is aberrantly activated in IPF and plays a vital role in myofibroblast differentiation and activation. Kinases such as Src initiate Wnt/β-catenin signaling by phosphorylating β-catenin at tyrosine residues, which facilitates β-catenin accumulation in the nucleus and promotion of fibrosis progression. Nintedanib has been approved for the treatment of IPF as a multitargeted tyrosine kinase inhibitor. Nintedanib has been demonstrated to directly block Src, and whether it attenuates pulmonary fibrosis through regulating the Wnt/β-catenin pathway remains unclear. In this study, we found that nintedanib attenuated myofibroblast activation through inhibiting the expression of genes downstream of Wnt signaling such as Cyclin D1, Wisp1, and S100a4. Further experiments showed that nintedanib inhibited Wnt3a-induced β-catenin nuclear translocation through suppressing Src kinase activation and β-catenin Y654 phosphorylation. Additionally, Src knockdown fibroblasts exhibited a phenotype similar to that of the nintedanib treatment group, and the inhibitory effects of nintedanib were consistent with those of the Src kinase inhibitor KX2-391. In summary, our study shows that nintedanib exhibits an anti-fibrosis effect, partly by inhibiting the Src/β-catenin pathway.