Abstract

Mast cells and fibroblasts are essential regulators in the progress of skin fibrosis, while little is known for treatments of skin fibrosis in targeting both mast cells and fibroblasts. Zafirlukast, a leukotriene receptor antagonist, has shown positive effect on various inflammatory and fibrotic diseases. However, whether zafirlukast plays a role in skin fibrosis by targeting mast cells and fibroblasts was still unclear. Therefore, our study further explored the potential therapeutic effect of zafirlukast for both mast cells and fibroblasts in skin fibrosis. Interestingly, our results showed that zafirlukast attenuated C48/80-triggered calcium influx and degranulation in mast cells by PLCγ-IP3R and PI3K/Akt signaling pathways in vitro. Meanwhile, our results also indicated that zafirlukast suppressed proliferation and migration of fibroblasts by TGF-β and NF-κB signaling pathways in vitro. Besides, our results suggested that zafirlukast alleviated keloid xenograft model by TGF-β and NF-κB signaling pathways in vivo. In addition, our results suggested zafirlukast inhibited BLM-induced SSc in murine model by TGF-β and NF-κB signaling pathways in vivo. In summary, our findings highlighted zafirlukast as a promising therapeutic agent, offering a novel approach to target both mast cells and fibroblasts, potentially leading to the treatment of skin fibrosis therapies.