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黄酮类化合物抗肝纤维化的作用机制及其相关信号通路
DOI: 10.12449/JCH260728
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：国文萱负责撰写论文；刘红梅负责修改论文；李成浩、金哲洙负责设计论文框架及指导论文撰写并最终定稿。
Mechanism of action of flavonoids in the treatment of hepatic fibrosis and related signaling pathways
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摘要: 肝纤维化发病率持续居高不下且缺乏特异性治疗药物，严重威胁人类健康。黄酮类化合物作为一类广泛存在于植物中的天然活性成分，具有抗氧化、抗炎、抗纤维化等多重生理功能，其抗肝纤维化作用已得到大量研究证实。在作用机制层面，黄酮类化合物可通过抑制肝星状细胞增殖分化并促进其凋亡、调控自噬水平、减少细胞外基质形成、调节肝星状细胞铁代谢等方式靶向肝星状细胞功能；同时可抑制肝脏慢性炎症反应、改善氧化应激状态、调节肠道菌群平衡及阻断上皮间质转化进程，多维度阻断纤维化进展。在信号通路层面，黄酮类化合物主要通过调控转化生长因子β1/母系抗十五表态蛋白同源物、Janus激酶/信号转导与转录激活因子等信号通路的异常激活，发挥抗纤维化效应。本文通过梳理黄酮类化合物抗肝纤维化的研究进展，以期为深入挖掘其药用潜力提供理论依据。Abstract: The incidence rate of hepatic fibrosis remains at a high level， and there is still a lack of specific therapeutic drugs， posing a serious threat to human health. As a type of natural active components widely present in plants， flavonoids have multiple physiological functions such as antioxidant， anti-inflammatory， and anti-fibrotic activities， and a large number of studies have confirmed the anti-hepatic fibrosis effect of flavonoids. As for the mechanism of action， flavonoids can target the functions of hepatic stellate cells by inhibiting their proliferation and differentiation， promoting their apoptosis， regulating the level of autophagy， reducing the formation of extracellular matrix， and regulating iron metabolism in hepatic stellate cells， and meanwhile， they can inhibit chronic liver inflammatory response， improve oxidative stress status， regulate intestinal flora balance， and block epithelial-mesenchymal transition， thereby blocking the progression of fibrosis through multiple dimensions. At the level of signaling pathways， flavonoids mainly exert an anti-fibrotic effect by regulating the abnormal activation of the signaling pathways such as transforming growth factor-β1/Smad， Janus kinase/signal transducer and activator of transcription， nuclear factor erythroid 2-related factor 2， nuclear factor-kappa B， phosphatidylinositol 3-kinase/protein kinase B， mitogen-activated protein kinase， Wnt/β-catenin， and adenosine 5'-monophosphate-activated protein kinase. This article summarizes the research advances in the anti-fibrotic effect of flavonoids， in order to provide a theoretical basis for further exploring their medicinal potential.
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Key words:
- Hepatic Fibrosis /
- Flavonoids /
- Signal Transduction
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注： HSC，肝星状细胞；ECM，细胞外基质；EMT，上皮间质转化。
图 1 黄酮类化合物治疗肝纤维化生物学功能示意图
Figure 1. Schematic diagram of biological functions of flavonoids in the treatment of hepatic fibrosis
注： 肝纤维化发病机制涉及多个相互关联的病理环节：当刺激因素损伤肝细胞和肝巨噬细胞后，肝细胞和肝巨噬细胞产生TGF-β、IL-6等调控因子，激活HSC向肌成纤维细胞转化，同时，肝细胞和肝巨噬细胞还可以通过EMT途径转化至肌成纤维细胞，受损的肝细胞可以产生ROS作用于临近正常肝细胞，使肝细胞进一步受损并产生MDA引起一系列炎症反应。肠道菌群失调可以产生脂多糖等促使肝巨噬细胞转化至M1型巨噬细胞，进而加重肝脏内炎症反应。此外，M1型巨噬细胞还可以生成TIMP，拮抗MMP对ECM的降解，HSC的自噬与铁蓄积也可以激活静止期HSC，加速其转化为肌成纤维细胞，同时，自噬还可以抑制激活态HSC的凋亡。ROS，活性氧；MDA，丙二醛；HSC，肝星状细胞；LPS，脂多糖；MMP，基质金属蛋白酶；TIMP，基质金属蛋白酶组织抑制因子；ECM，细胞外基质；EMT，上皮间质转化；TGF-β，转化生长因子β；IL-6，白细胞介素6。
图 2 肝纤维化病理机制示意图
Figure 2. Schematic diagram of pathological mechanisms of liver fibrosis
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