摘要Keloid is a benign skin tumor characterized by its cell hyperproliferative activity,invasion into normal skin,uncontrolled growth,overproduction and deposition of extracellular matdces and high recurrence rate after various therapies.Nintedanib is a receptor tyrosine kinase inhibitor targeting VEGF,PDGF,FGF,and TGF-β receptors with proved efficacy in anti-angiogenesis and in treating vadous types of cancers.In this study,we investigated the effects of nintedanib on keloid fibroblasts in both in vitro and ex vivo models.Keloid fibroblasts were prepared from 54 keloid scar samples in active stages collected from 49 patients.We found that nintedanib (1-4 μM) dose-dependently suppressed cell proliferation,induced G0/G1 cell cyde arrest,and inhibited migration and invasion of keloid fibroblasts.The drug also significantly inhibited the gene and protein expression of collagen Ⅰ (COL-1) and Ⅲ (COL-3),fibronectin (FN),and connective growth factor (CTGF),as well as the gene expression of other pathological factors,such as alpha smooth muscle actin (α-SMA),plasminogen activator inhibitor-1 (PAl-1),FK506-binding protein 10 (FKBP10),and heat shock protein 47 (HSP47) in keloid fibroblasts.Furthermore,nintedanib treatment significantly suppressed the phosphorylation of p38,JNK,ERK,STAT3,and Smad,enhanced endocytosis of various growth factor receptors.Using an ex vivo tissue explant model,we showed that nintedanib significantly suppressed cell proliferation,migration,and collagen production.The drug also significantly disrupted microvessel structure ex vivo.In summary,our results demonstrate that nintedanib is likely to become a potential targeted drug for keloid systemic therapy.