非编码RNA介导TGF-β_(1)/Smads信号通路与肝纤维化及中药活性成分干预研究进展

Non-coding RNA-mediated TGF-β_(1)/Smads Signaling Pathway and Liver Fibrosis,and Intervention by Active Components of Chinese Medicinal:A Review

肝纤维化是对致使肝脏慢性损伤的一种伤口愈合反应,其病理特征是细胞外基质(ECM)合成和降解失衡,导致ECM在肝内过度沉积。如果不加以干预,可能会发展为肝硬化和肝细胞癌。肝星状细胞(HSC)的激活是导致肝纤维化的中心事件,活化的HSC会转分化为产生ECM蛋白的肌成纤维细胞。促纤维化因子转化生长因子-β_(1)(TGF-β_(1))对HSC的活化起到诱导作用,TGF-β_(1)/Smads信号通路是重要的促肝纤维化途径之一。非编码RNA(ncRNA)是指基因在转录过程中不编码蛋白质的RNA,在基因转录后环节起着重要调控作用。大量研究表明,肝纤维化发生与ncRNA的异常表达有紧密联系,ncRNA能通过调控TGF-β_(1)信号转导参与HSC活化,进而影响肝纤维化进程。微小RNA(miRNA)介导TGF-β_(1)/Smads信号通路既可以促进肝纤维化,也可发挥抗肝纤维化作用;长链非编码RNA(lncRNA)不仅结合靶基因促进肝纤维化的发展,还通过充当竞争性内源性RNA结合miRNA促进TGF-β_(1)信号转导;环状RNA(circRNA)以海绵作用结合miRNA调控TGF-β_(1)/Smads途径,抑制HSC活化而抗肝纤维化。中药在预防和治疗肝纤维化发挥着重要作用,其含有的活性成分可通过调控miRNA表达抑制TGF-β_(1)/Smads途径,从而改善肝纤维化。该文综述了近年来miRNA、lncRNA和circRNA介导TGF-β_(1)/Smads信号通路在肝纤维化中的作用和机制,并简要概述了中药活性成分通过调控miRNA介导TGF-β_(1)/Smads信号通路抗肝纤维化,为今后肝纤维化临床治疗和新型药物研发提供重要参考。

Liver fibrosis is a wound healing response that occurs in the setting of chronic liver injury and is caused by imbalance in the synthesis and degradation of extracellular matrix(ECM). If left untreated,it can progress to liver cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cell(HSC)is now well established as a central driver of liver fibrosis. The activated HSC will transform into myofibroblasts that produce ECM protein. Transforming growth factor-β_(1)(TGF-β_(1))can induce the activation of hepatic stellate cell(HSC),and TGF-β_(1)/Smads signaling pathway is one of the important pathways to promote liver fibrosis. Non-coding RNA(ncRNA)does not encode proteins during the transcription but plays an important regulatory role in the post-transcriptional process of genes. Accumulating evidence shows that the occurrence of liver fibrosis is closely related to the abnormal expression of ncRNA which participates in the activation of HSC by regulating TGF-β_(1)signal transduction and then affects the process of liver fibrosis. MiRNA-mediated TGF-β_(1)/Smads signaling pathway can not only promote liver fibrosis but also play a role in anti-fibrosis. Long non-coding RNA(lncRNA)not only promotes the development of liver fibrosis by binding to target genes but also enhances TGF-β_(1)signal transduction by acting as competitive endogenous RNA. circular RNA(circRNA)acts as a “sponge” to regulate TGF-β_(1)/Smads pathway,thereby inhibiting HSC activation and exerting the anti-liver fibrosis effect. Chinese medicinal plays an essential part in the prevention and treatment of liver fibrosis,and the active components can inhibit TGF-β_(1)/Smads pathway by regulating the expression of miRNA,thus alleviating liver fibrosis. This article reviews the role and mechanism of miRNA-,lncRNA-and circRNA-mediated TGF-β_(1)/Smads signaling pathway in liver fibrosis and summarizes the anti-liver fibrosis effect of active components of Chinese medicinals by regulating miRNA-mediated TGF-β_(1)/Smads signaling pathway,which can serve as a reference for clinical treatment of liver fibrosis and the development of new drugs.