Activated hepatic stellate cells (HSCs) are the major cell type involved in the deposition of extracellular matrix (ECM) during the development of hepatic fibrosis. In this study, we revealed that left-right determination factor 2 (LEFTY2), one of the proteins belonging to the transforming growth factor-β (TGF-β) protein superfamily, was remarkedly decreased in human hepatic fibrosis tissues and in a carbon tetrachloride (CCl₄)-induced liver fibrosis mouse model. In addition, TGF-β1 treatment markedly reduced the level of LEFTY2 in HSCs. Importantly, overexpression of LEFTY2 suppressed the activation and proliferation of HSCs. LEFTY2 inhibited the expression of TGF-β1-induced fibrosis-associated genes (α-SMA and COL1a1) in human (LX-2) and rat (HSC-T6) HSC cell lines in vitro. Mechanistically, we demonstrated, for the first time, the role of LEFTY2 in inhibiting TGF-β1/Smad3 signaling, suggesting that there is a mutual antagonism between LEFTY2 and TGF-β1/Smad3 signaling during liver fibrosis. Similarly, we observed that LEFTY2 has a negative effect on its downstream genes, including c-MYC, CDK4, and cyclin D1, in liver fibrosis. Collectively, our data strongly indicated that LEFTY2 plays an important role in controlling the proliferation and activation of HSCs in the progression of liver fibrosis and this could be a potential therapeutic target for its treatment.

肝星状细胞（HSC）活化是肝纤维化发展过程中参与细胞外基质（ECM）沉积的主要细胞类型。在这项研究中，我们揭示了在人类肝纤维化组织和四氯化碳中，属于转化生长因子-β（TGF-β）蛋白超家族的一种蛋白质左右决定因子2（LEFTY2）明显减少。 （CCL ₄）诱导的肝纤维化小鼠模型。此外，TGF-β1处理可显着降低HSC中LEFTY2的水平。重要的是，LEFTY2的过表达抑制了HSC的激活和增殖。LEFTY2抑制了人（LX-2）和大鼠（HSC-T6）HSC细胞系中TGF-β1诱导的纤维化相关基因（α-SMA和COL1a1）的表达。从机制上讲，我们首次证明了LEFTY2在抑制TGF-β1/ Smad3信号传导中的作用，表明在肝纤维化过程中，LEFTY2和TGF-β1/ Smad3信号传导之间存在相互拮抗作用。同样，我们观察到LEFTY2对其肝纤维化中的下游基因（包括c-MYC，CDK4和cyclin D1）具有负面影响。总的来说，