MiR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b was upregulated in HSCs but not in hepatocytes during hepatic fibrogenesis in vivo and upon culture-activation in vitro. Inhibition of miR-125b suppressed the expression of profibrogenic genes in culture-activated primary HSCs and reduced the basal and transforming growth factor beta (TGF-β)-induced α-SMA expression and cell contraction of immortalized HSC cell line. In contrast, ectopic expression of miR-125b promoted α-SMA expression and HSC contraction. Moreover, antagonizing miR-125b in vivo significantly alleviated liver fibrosis in CCl₄-treated mice. Mechanistically, overexpression of miR-125b in HSC enhanced RhoA activity by directly targeting StAR-related lipid transfer (START) domain containing 13 (Stard13), a RhoA specific GTPase-activating protein, whereas knockdown of miR-125b abrogated RhoA activation. Furthermore, inhibition of RhoA or its downstream molecules, Mrtf-A and Srf, attenuated the miR-125b-induced α-SMA expression and HSC contraction. Therefore, our findings identify a miR-125b-Stard13-RhoA-α-SMA signaling cascade in HSC and highlight its importance in hepatic fibrosis.

MiR-125b在不同疾病中经常失调。肝星状细胞（HSC）的激活是肝纤维化过程中的关键事件。然而，miR-125b在HSC活化和肝纤维化中的功能及其潜在机制仍是未知的。在这里，我们显示了miR-125b在体内肝纤维化过程中以及体外培养激活后在HSCs中表达上调，但在肝细胞中没有上调。抑制miR-125b可抑制培养激活的原代HSC中纤维原基因的表达，并降低基础和转化生长因子β（TGF-β）诱导的永生HSC细胞系的α-SMA表达和细胞收缩。相反，miR-125b的异位表达促进了α-SMA表达和HSC收缩。而且，拮抗miR-125b体内显着减轻了CCl ₄处理小鼠的肝纤维化。从机制上讲，miR-125b在HSC中的过表达通过直接靶向含有13（Stard13）（一种RhoA特异性GTPase激活蛋白）的StAR相关脂质转移（START）结构域而增强了RhoA活性，而敲低miR-125b则废除了RhoA激活。此外，对RhoA或其下游分子Mrtf-A和Srf的抑制作用减弱了miR-125b诱导的α-SMA表达和HSC收缩。因此，我们的发现确定了HSC中的miR-125b-Stard13-RhoA-α-SMA信号传导级联反应，并突出了其在肝纤维化中的重要性。