大多数慢性肝病会进展为肝纤维化，若不加治疗会导致肝硬化和肝细胞癌。微小RNA（miRNA）靶向治疗已成为治疗疾病的吸引人的方法之一。本研究中，我们调查了miR-155抑制在胆总管结扎（BDL）小鼠肝纤维化模型中的治疗效果，并评估了miR-155在慢性肝纤维化中的作用，使用miR-155缺失（miR-155敲除）小鼠。我们发现在肝硬化患者和BDL-和CCl4诱导的小鼠肝纤维化模型中，肝脏miR-155表达增加。miR-155敲除小鼠CCl4施用或BDL后肝纤维化显著减少。为了评估miR-155抑制的治疗潜力，我们在体内接种了rAAV8-anti-miR-155 tough decoy，明显减轻了BDL中肝损伤和纤维化。与对照小鼠相比，anti-miR-155治疗小鼠的BDL诱导的转化生长因子β（TGF-β）、p-SMAD2 / 3和p-STAT3蛋白水平减弱。miR-155缺失小鼠的肝星状细胞表现为活化和基质标记物表达的减弱。体外实验中，miR-155过度表达和沉默功能的研究表明，miR-155部分通过STAT3信号途径调节星状细胞的活化。我们的研究表明miR-155是肝纤维化的关键调节因子，可能成为减轻纤维化进展的潜在治疗靶点。© 2023 The Authors.

Most chronic liver diseases progress to liver fibrosis, which, when left untreated, can lead to cirrhosis and hepatocellular carcinoma. MicroRNA (miRNA)-targeted therapeutics have become attractive approaches to treat diseases. In this study, we investigated the therapeutic effect of miR-155 inhibition in the bile duct ligation (BDL) mouse model of liver fibrosis and evaluated the role of miR-155 in chronic liver fibrosis using miR-155-deficient (miR-155 knockout [KO]) mice. We found increased hepatic miR-155 expression in patients with cirrhosis and in the BDL- and CCl4-induced mouse models of liver fibrosis. Liver fibrosis was significantly reduced in miR-155 KO mice after CCl4 administration or BDL. To assess the therapeutic potential of miR-155 inhibition, we administered an rAAV8-anti-miR-155 tough decoy in vivo that significantly reduced liver damage and fibrosis in BDL. BDL-induced protein levels of transforming growth factor β (TGF-β), p-SMAD2/3, and p-STAT3 were attenuated in anti-miR-155-treated compared with control mice. Hepatic stellate cells from miR-155 KO mice showed attenuation in activation and mesenchymal marker expression. In vitro, miR-155 gain- and loss-of-function studies revealed that miR-155 regulates activation of stellate cells partly via STAT3 signaling. Our study suggests that miR-155 is the key regulator of liver fibrosis and might be a potential therapeutic target to attenuate fibrosis progression.© 2023 The Authors.