柚皮素是一种潜在的免疫调节剂，可通过抑制cGAS-STING通路来抑制肝纤维化。
Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.
作者信息
Chen Li, Xia Siwei, Wang Shuqi, Zhou Yuanyuan, Wang Feixia, Li Zhanghao, Li Yang, Kong Desong, Zhang Zili, Shao Jiangjuan, Xu Xuefen, Zhang Feng, Zheng Shizhong
机构信息
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Chinese Medicine Modernization and Big Data Research Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
出版信息
J Clin Transl Hepatol. 2023 Feb 28;11(1):26-37. doi: 10.14218/JCTH.2022.00120. Epub 2022 Apr 28.
BACKGROUND AND AIMS
Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.
METHODS
The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS .
RESULTS
Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.
CONCLUSIONS
Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.
背景与目的
柚皮素是一种抗炎类黄酮，已在慢性肝病研究中有所涉及。其抗纤维化活性的具体机制尚需进一步研究。本研究聚焦于肝星状细胞中的环磷酸鸟苷-磷酸腺苷合成酶（cGAS）通路，以阐明柚皮素的抗纤维化机制。
方法
利用基因表达综合数据库分析cGAS-干扰素基因刺激因子（STING）通路与肝纤维化之间的关系。采用组织病理学、免疫组织化学、荧光染色、蛋白质印迹法和聚合酶链反应，评估临床肝组织样本和小鼠肝脏中与cGAS通路相关的基因和蛋白表达水平。进行分子对接以评估柚皮素与cGAS之间的关系，并通过蛋白质印迹法研究cGAS下游炎症因子的表达。
结果
临床数据库分析表明，cGAS-STING通路参与慢性肝病的发生。柚皮素可改善四氯化碳（CCl）处理小鼠的肝损伤和肝纤维化，减少胶原沉积和cGAS表达，并抑制炎症。分子对接发现，cGAS可能是柚皮素的直接靶点。与此结果一致，我们验证了柚皮素对活化肝星状细胞（HSCs）的抑制作用。通过使用cGAS特异性激动剂双链（ds）DNA，我们发现柚皮素可减弱dsDNA对cGAS及其炎症因子的激活作用。我们证实，柚皮素抑制cGAS-STING通路，从而减少HSCs分泌炎症因子以改善肝纤维化。
结论
阻断cGAS-STING通路有助于逆转纤维化进程。柚皮素具有作为抗肝纤维化药物的潜力。
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