目的 研究黄芪甲苷（astragaloside Ⅳ，AS-Ⅳ）抗肝纤维化的疗效及分子机制。方法 采用sc 40%四氯化碳花生油联合10%乙醇饲喂的方式构建大鼠肝纤维化模型，判断造模成功后，随机分为空白组、模型组和AS-Ⅳ低、高剂量（20、40 mg/kg）组，各给药组ig相应药物，空白组和模型组ig等体积生理盐水，给药6周后采用苏木素-伊红（HE）染色、Masson染色观察肝组织病理学变化；通过检测血清中丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天冬氨酸氨基转移酶（aspartate aminotransferase，AST）活性及肝纤维化标志物水平以评价AS-Ⅳ抗肝纤维化的疗效；采用免疫组化、Western blotting、qRT-PCR检测肝星状细胞（hepatic stellate cells，HSCs）活化标志物α-平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）及I型胶原（CollagenⅠ）的表达；采用Western blotting及qRT-PCR检测影响HSCs活化的CXC基序趋化因子配体12（C-X-C motif chemokine ligand 12，CXCL12）/CXC基序趋化因子受体4（C-X-C motif chemokine receptor 4，CXCR4）信号轴及硫氧还蛋白互作蛋白（thioredoxin-interacting protein，TXNIP）/NOD样受体热蛋白结构域相关蛋白3（NOD-like receptor thermal protein domain associated protein 3，NLRP3）炎性体路径上关键因子的表达。结果 与空白组比较，模型组大鼠血清中ALT、AST活性及透明质酸（hyaluronic acid，HA）水平显著升高（P＜0.05、0.01），肝组织炎症及胶原纤维沉积增加；与模型组比较，AS-Ⅳ显著降低血清中ALT、AST活性及HA水平（P＜0.05、0.01），减轻肝组织炎症及纤维化。此外，与空白组比较，模型组肝组织α-SMA和Collagen I表达显著升高（P＜0.01），CXCL12/CXCR4信号轴显著上调（P＜0.05、0.01），TXNIP、NLRP3、ASC、IL-1β高表达（P＜0.05、0.01）；与模型组比较，AS-Ⅳ显著抑制肝组织α-SMA、Collagen I表达（P＜0.05、0.01），抑制CXCL12/CXCR4信号轴（P＜0.01），下调TXNIP、NLRP3、ASC、IL-1β表达（P＜0.05、0.01）。结论AS-Ⅳ可显著改善四氯化碳联合乙醇诱导的大鼠肝损伤，减轻肝纤维化，并可抑制HSCs活化，其调控机制可能与抑制CXCL12/CXCR4信号轴和TXNIP/NLRP3炎性体路径有关。

Objective To study the therapeutic effect and molecular mechanism of astragaloside IV (AS-IV) on liver fibrosis. Methods A rat model of liver fibrosis was established by sc 40% carbon tetrachloride peanut oil and feeding 10% ethanol. After judging the success of the model, rats were randomly divided into blank group, model group, AS-Ⅳ low- and high-dose (20 and 40 mg/kg) groups. The corresponding drugs were given to each group, blank group and model group were given equal volumes of normal saline. After six weeks of administration, hematoxylin eosin (HE) staining and Masson staining were used to observe the pathological changes of liver tissue; To evaluate the therapeutic effect of AS-Ⅳ on liver fibrosis, the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and levels of liver fibrosis markers were measured; Immunohistochemistry, Western blotting, and qRT-PCR were used to detect expressions of activation markers of hepatic stellate cells (HSCs) such as α-smooth muscle actin (α-SMA and Collagen I; Western blotting and qRT-PCR were used to detect key factors expressions in CXC motif chemokine ligand 12 (CXCL12)/CXC motif chemokine receptor 4 (CXCR4) signal axis and thioredoxin interacting protein (TXNIP)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway that affect the activation of HSCs. Results Compared with blank group, the activities of ALT, AST and level of hyaluronic acid (HA) in serum of rats in model group were significantly increased (P < 0.05, 0.01), liver histopathological inflammation and collagen fiber deposition were increased; Compared with model group, AS-Ⅳ significantly decreased activities of ALT, AST and level of HA level in serum (P < 0.05, 0.01), reduced liver inflammation and fibrosis. In addition, compared with blank group, expressions of α-SMA and Collagen I in liver tissue of model group was significantly increased (P < 0.01), CXCL12/CXCR4 signal axis were significantly upregulated (P < 0.05, 0.01), TXNIP, NLRP3, ASC, IL-1β were high expression (P < 0.05, 0.01); Compared with model group, AS-Ⅳ significantly inhibited expressions of α-SMA and Collagen I (P < 0.05, 0.01), inhibited CXCL12/CXCR4 signal axis (P < 0.01), downregulated TXNIP, NLRP3, ASC and IL-1β expressions (P < 0.05, 0.01). Conclusion AS-Ⅳ could significantly improve carbon tetrachloride combined with ethanol induced liver injury in rats, alleviate liver fibrosis, and inhibit the activation of HSCs. The regulatory mechanism may be related to the inhibition of CXCL12/CXCR4 signal axis and TXNIP/NLRP3 inflammatory pathway.

四川省科技重点研发项目（2022YFS0409）；成都中医药大学“杏林学者”学科人才科研提升计划（BSH2020014）