Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology with poor prognosis. The currently approved antifibrotic drugs only decelerate functional decline and fail to reverse established fibrosis or extend survival. Binimetinib, a highly selective and noncompetitive MEK1/2 inhibitor, has been approved for clinical use in malignancies such as melanoma and non–small cell lung cancer. This study aims to evaluate the therapeutic effects of binimetinib on IPF and to explore its underlying mechanism. Methods In this study, the antifibrotic effects and underlying mechanisms of binimetinib were evaluated both in vivo and in vitro. Results In vivo, experiments demonstrated that binimetinib markedly ameliorated bleomycin-induced pulmonary fibrosis in mice, as evidenced by the reduction in hydroxyproline content (184.3±25.4 µg in bleomycin group vs. 94.6±9.8 µg in high-dose binimetinib group, P<0.001) and fibrotic area (14.8%±2.9% in bleomycin group vs. 5.4%±1.6% in high-dose binimetinib group, P<0.001). In vitro, binimetinib directly targeted the MEK/ERK signaling cascade and concurrently inhibited both the TGF-β/SMAD and TGF-β/non-SMAD pathways, thereby suppressing fibroblast proliferation, migration, activation, and extracellular matrix deposition. Furthermore, binimetinib attenuated the overall activation of pulmonary macrophages through inhibition of the JAK/STAT pathway. Conclusions In summary, binimetinib exerted potent anti-inflammatory and antifibrotic effects by suppressing the activation of both fibroblasts and pulmonary macrophages, ultimately mitigating bleomycin-induced pulmonary fibrosis in mice.