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非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)逐渐成为发病率最高的慢性肝病类型。NASH发病常常伴随全身代谢综合征,疾病进展具有发生肝硬化甚至肝癌的高风险。然而,目前临床上尚无一种获批的针对NASH的有效治疗药物。我们的最新研究结果发现,天然免疫重要分子CFLAR[CASP8 and FADD(Fas-associating protein with death domain)-like apoptosis regulator]直在NASH疾病进程中的关键负调控作用。深入的分子机制探索证实,CFLAR接靶向激酶MAP3K5[mitogen-activated protein kinase kinase kinase 5,也称为ASK1(apoptosis signal-regulating kinase 1)]并阻断其N-端二聚化,从而抑制ASK1和激酶MAPK8[mitogen-activated protein kinase 8,也称为JNK1(c-Jun N-terminal kinase 1)]的信号通路。此外,我们鉴定出源于CFLAR的一个小肽片段(S1)可以有效发挥CFLAR对ASK1的抑制作用。应用CFLAR(S1)治疗可有效改善并逆转小鼠和猴子中的NASH及并发的代谢综合征。综上所述,我们发现,CFLAR是控制NASH疾病进展的关键抑制子。CFLAR(S1)特异性抑制ASK 1激活的作用机制,为开发或筛选NASH的靶向治疗药物提供了可行的新方案。
Nonalcoholic steatohepatitis (NASH) has gradually become the most prevalent type of chronic liver disease. NASH pathogenesis is often accompanied by systemic metabolic syndrome, disease progression has the risk of cirrhosis and even liver cancer. However, there is currently no clinically valid therapeutic drug for NASH. Our latest findings show that the key negative regulator of the innate immunity important molecule CFLAR [CASP8 and FADD (Fas-associating protein with death domain) -like apoptosis regulator] in NASH disease progression. In-depth molecular mechanisms to explore confirmed that CFLAR then target kinase MAP3K5 [mitogen-activated protein kinase kinase kinase 5, also known as ASK1 (apoptosis signal-regulating kinase 1)] and block its N-terminal dimerization, thereby inhibiting ASK1 And the kinase-activated protein kinase 8 (also known as JNK1 (c-Jun N-terminal kinase 1)] signaling pathway. In addition, we identified a small peptide fragment (S1) derived from CFLAR that effectively exerts the inhibitory effect of CFLAR on ASK1. Treatment with CFLAR (S1) effectively improves and reverses NASH and concurrent metabolic syndrome in mice and monkeys. Taken together, we found that CFLAR is a key inhibitor of disease progression in NASH. The mechanism by which CFLAR (S1) specifically inhibits ASK1 activation provides a viable new protocol for the development or screening of targeted therapies for NASH.