Binimetinib Attenuates Skin Fibrosis by Inhibiting the TGF‐β1 Signaling Pathway

Abstract

Background: Dermatofibrosis diseases (e.g., keloids) are abnormal pathological results of the tissue healing process. They are characterized by the excessive proliferation of fibroblasts in the dermis and the excessive deposition of extracellular matrix. Existing treatments for dermatofibrosis have not achieved satisfactory results. The therapeutic efficacy of Binimetinib as a clinical agent for treating cutaneous malignancies in the field of fibrosis has not been extensively studied. Therefore, this study aims to investigate the antifibrotic activity of Binimetinib both in vitro and in vivo against dermal fibrosis, as well as elucidate its underlying mechanism. Methods: In this study, we explored the potential effects and underlying mechanisms of Binimetinib on dermal fibrosis both in vitro and in vivo. In the in vitro experiments, we applied the Cell Counting Kit-8 (CCK-8) assay, wound healing assay, and western blotting to examine the inhibitory effects of Binimetinib on the proliferation, migration, and activation of mouse primary dermal fibroblasts (PSFs) and human keloid fibroblasts (KFs). In the in vivo experiments, we established a bleomycin mouse dermal fibrosis model and a nude mouse subcutaneous keloid model to verify the inhibitory effect of Binimetinib on dermal thickening in bleomycin model mice and on growth in subcutaneous keloid model in nude mice. Additionally, we investigated the expressions of proteins related to the transforming growth factor-β1 (TGF-β1) signaling pathway. Results: In vitro experiments showed that Binimetinib effectively suppressed the proliferation, migration, and activation of KFs and PSFs in a dose-dependent manner (p < 0.05). In vivo experiments revealed that Binimetinib attenuated dermal thickening induced by bleomycin (BLM), reduced hydroxyproline content, and reduced the expression of fibrosis markers in a bleomycin-induced dermal fibrosis model (p < 0.05). Moreover, in a nude mouse subcutaneous keloid model, Binimetinib not only inhibited keloid proliferation and weight gain but also suppressed the expression of fibrosis markers (p < 0.05). Further mechanistic studies indicated that Binimetinib inhibited both TGF-β1/recombinant SMAD family member (Smad) signaling and TGF-β1/non-Smad signaling pathways associated with fibrosis (p < 0.05). Conclusions: In summary, our results confirm that Binimetinib effectively suppresses fibrosis both in vivo and in vitro by inhibiting the TGF pathway, demonstrating significant potential for fibrosis treatment.