Peficitinib suppresses diffuse-type tenosynovial giant cell tumor by targeting TYK2 and JAK/STAT signaling  

作　　者：Shan Lu Chenxi Cao Wenjia Zhang Jiayi Li Jingli Yang Zisheng Huang Zhijun Wu Baitao Liu Hongjie Huang Haijun Wang Yongjian Wang Dingge Liu Zhihua Zhang Kaiping Liu Gang Yang Xi Gong Hui Dai Yingjia Li Erdan Dong Xin Zhang Yan Zhang 

机构地区：[1]Institute of Cardiovascular Sciences,School of Basic Medical Sciences,Peking University Health Science Center,Department of Cardiology and Instituteof Vascular Medicine,Peking University Third Hospital,State Key Laboratory of Vascular Homeostasis and Remodeling,Peking University,Beijing 100191,China [2]Department of Sports Medicine,Peking University Third Hospital,Institute of Sports Medicine of Peking University,Beijing 100191,China [3]Beijing Key Laboratory of Sports Injuries,Beijing 100191,China [4]Engineering Research Center of Sports Trauma Treatment Technology and Devices,Ministry of Education,Beijing 100191,China [5]State Key Laboratory of Membrane Biology,Institute of Molecular Medicine,College of Future Technology,Peking University,Beijing 100871,China [6]Peking University Health Science Centre,Peking University,Beijing 100871,China [7]Department of Immunology,School of Basic Medical Sciences,NHC Key Laboratory of Medical Immunology,Peking University,Beijing 100871,China [8]Research Center for Cardiopulmonary Rehabilitation,Universityof Health and Rehabilitation Sciences Qingdao Hospital(Qingdao Municipal Hospital),Schoolof Health and Life Sciences,Universityof Health and Rehabilitation Sciences,Qingdao 266071,China [9]Research Unitof MedicalScience Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases,Chinese Academy of Medical Sciences,Haihe Laboratory of Cell Ecosystem,Beijing 100191,China [10]Institute of Cardiovascular Diseases,The First Affiliated Hospital of Dalian Medical University,Dalian 116011,China

出　　处：《Science China(Life Sciences)》2025年第3期593-609,共17页中国科学(生命科学英文版)

基　　金：supported by grants from the National Key R&D Program of China(2021YFF0501401,2018YFA0800501);National Natural Science Foundation of China(82325004,92168114,82172447);Haihe Laboratory of Cell Ecosystem Innovation Fund(HH22KYZX0047).

摘　　要：Diffuse-type tenosynovial giant cell tumor(dTGCT)is a destructive but rare benign proliferative synovial neoplasm.Although surgery is currently the main treatment modality for dTGCT,the recurrence risk is up to 50%.Therefore,there is a great need for effective drugs against dTGCT with minor side effects.The Janus kinase(JAK)/signal transducer and activator of transcription(STAT)signaling plays a central role in rheumatoid arthritis(RA),a disease with similar characteristics as dTGCT,but its function in dTGCT remains unknown.dTGCT fibroblast-like synoviocytes(FLS)and macrophages were isolated from 10 synovial tissue samples from dTGCT patients for the screening and validation of the five clinically approved JAK inhibitors to treat RA against dTGCT.Cell viability,cell death,inflammation and the activity of the JAK family members of cultured dTGCT FLS(both 2-D and 3-D)and macrophages were investigated for the efficacy of the JAK inhibitors.Here,we found that similar to RA,JAK/STAT signaling was markedly activated in the dTGCT synovium.Of the 5 JAK inhibitors,peficitinib was shown to have the most potency in addressing some of the pathological responses of dTGCT FLS and macrophages.The potency of peficitinib was much higher than pexidartinib,which is the only FDA-approved drug for dTGCT.Mechanistically,peficitinib inhibited tyrosine kinase 2(TYK2),a JAK family member necessary for the pathological progression of dTGCT FLS and macrophages.In summary,we not only revealed JAK/STAT(especially TYK2)signaling as the major mechanism underlying dTGCT,but also identified peficitinib as a promising drug against dTGCT.

关 键 词：dTGCT JAK/STAT signaling peficitinib TYK2 FLS MACROPHAGES 

分 类 号：R738.5[医药卫生—肿瘤]