Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

• Published in: International journal of molecular sciences 2021-02, Vol.22 (4), p.1985
• Main Authors: Li, Xiaohe, Ma, Ling, Huang, Kai, Wei, Yuli, Long, Shida, Liu, Qinyi, Zhang, Deqiang, Wu, Shuyang, Wang, Wenrui, Yang, Guang, Zhou, Honggang, Yang, Cheng
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Autophagy - drug effects; Bleomycin; Cell Movement - drug effects; Down-Regulation - drug effects; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - metabolism; Male; Mice; Mice, Inbred C57BL; myofibroblasts; NIH 3T3 Cells; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; pulmonary fibrosis; Pyridines - pharmacology; Pyridines - therapeutic use; regorafenib; Signal Transduction; Smad Proteins - metabolism; TGF-β1 signaling pathway; TOR Serine-Threonine Kinases - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22041985

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.