内容来源于Cell Death and Disease（if6.304）慢性炎症是持续数月的免疫反应，但无论病因如何，慢性炎症极易引起肝纤维化，最终导致肝硬化和肝癌。人参皂苷Rg3（20R-ginsenoside Rg3，G-Rg3）是我国拥有自主知识产权的1类抗癌新药，主要用于临床原发性肺癌、肝癌的治疗及改善肿瘤患者的气虚症状，从而提高机体的免疫功能。近期，吉林农业大学李伟教授研究团队发表在“Cell Death and Disease”题为“Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway”的论文探讨了G-Rg3对炎症介导的肝脏自噬的抑制作用，以抑制硫代乙酰胺（thioacetamide，TAA）诱导的亚急性和慢性肝损伤所致的肝纤维化。TAA作为一种常见的的肝毒剂，与人病毒性肝炎引起的肝硬化有更多的相似性，更能准确再现临床肝硬化的疾病特点。因此，团队使用TAA肝损伤模型来评估G-Rg3在预防和治疗肝纤维化的临床价值潜力。研究结果表明：G-Rg3治疗逆转了肝纤维化及胶原纤维沉积，对TAA引起的肝损伤具有保护作用。同时，G-Rg3可以下调HSCs激活标志物（α-SMA）蛋白表达及促纤维化因子（TGF-β1）分泌。为了进一步阐释其发挥疗效的分子机制，团队利用系统药理学手段显示PI3K/AKT及mTOR介导的自噬通路可能是G-Rg3阻止TAA诱导的肝脏纤维化的关键靶标。该研究表明G-Rg3可能代表了一种新兴有效的方法而发挥抗纤维化作用，也为探索人参皂苷在肝纤维化早期治疗策略上提供了新思路。
Cell Death and Disease(2020, 10.1038/s41419-020-2597-7)Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway Inflammation and autophagy occur during hepatic fibrosis development caused by various pathogens, and effectively curbing of autophage may delay the occurrence of hepatic fibrosis. The current study aimed to unravel the inhibitory effects of Ginsenoside Rg3 (G-Rg3) on inflammation-mediated hepatic autophagy to curb hepatic fibrosis caused by thioacetamide (TAA)-induced subacute and chronic hepatic injury. TAA is mainly metabolized in the liver to cause liver dysfunction. After intraperitoneal injection of TAA for 4 or 10 weeks (TAA-chronic mouse models), severe inflammatory infiltration and fibrosis occurred in the liver. Treatment with G-Rg3 alleviated hepatic pathological changes and reversed hepatic fibrosis in the TAA-chronic models with decreased deposition of collagen fibers, reduced expression of HSCs activation marker (α-SMA), and reduced secretion of profibrogenic factors (TGF-β1). G-Rg3 decreased expressions of autophagy-related proteins in mice of TAA-chronic models. Notably, G-Rg3 inhibited the survival of activated rat hepatic stellate cells (HSC-T6), but had no cytotoxicity on human hepatocytes (L02 cell lines). G-Rg3 dose dependently inhibited autophagy in vitro with less expression of p62 and fewer LC3a transformation into LC3b in inflammatory inducer lipopolysaccharide (LPS)-induced rat HSC-T6 cells. Furthermore, G-Rg3 enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in vivo and in vitro. Besides, mTOR inhibitor Rapamycin and PI3K inhibitors LY294002 were employed in LPS-treated HSC-T6 cell cultures to verify that Rg3 partially reversed the increase in autophagy in hepatic fibrosis in vitro. Taken together, G-Rg3 exerted anti-fibrosis effect through the inhibition of autophagy in TAA-treated mice and LPS-stimulated HSC-T6 cells. These data collectively unravel that G-Rg3 may serve a promising anti-hepatic fibrosis drug.
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