凋亡信号调节激酶-1抑制剂在非酒精性脂肪性肝炎中的研究进展

Research progress of apoptosis signal regulating kinases-1 and its inhibitors in non-alcoholic steatohepatitis

非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)是最常见的慢性肝病,当前未见有效疗法。凋亡信号调节激酶-1(apoptosis signal regulating kinases 1,ASK-1)是细胞丝裂原活化蛋白激酶激酶激酶(mitogen-activated protein kinase kinase kinases,MAPKKKs)家族成员之一,当机体受到细胞内活性氧簇应激、内质网应激、钙内流和细胞外炎症等信号刺激时,ASK-1激活c-Jun氨基末端激酶(c-Jun amino terminal kinasec,JNK)和p38 MAPK通路,从而促进细胞增殖、分化、凋亡以及炎症因子的产生,诱发NASH、纤维化等疾病,因此可通过抑制ASK-1的活性来治疗NASH。本文对当前NASH的治疗手段、ASK-1结构和作用机制以及近年ASK-1抑制剂治疗NASH的研究进展进行综述,旨在为该类抑制剂的设计与开发提供参考。

Non-alcoholic steatohepatitis (NASH)is the most common chronic liver disease.However,the treatment of NASH remains challenging.Apoptosis signal regulating kinases-1 (ASK-1)is a member of mitogen-activated protein kinase kinase kinases (MAPKKKs).When the body is stimulated by reactive oxygen species,endoplasmic reticulum stress,calcium influx and extracellular inflammatory signals,c-Jun amino terminal kinases (JNK) and p38 MAPK wiube activated,which then promotes cell proliferation,differentiation,apoptosis and production of inflammatory factors,and causes NASH,fibrosis and other diseases.Therefore,ASK-1 inhibitors can be used to treat NASH.This paper reviews the current treatment methods of NASH,the structure and mechanism of ASK-1,and the research progress of ASK-1 inhibitors in the treatment of NASH in recent years,which aims to explore the guiding significance for the design and development of ASK-1 inhibitors.