Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou Key Laboratory of Chirality Research on Active Components of Traditional Chinese Medicine, The Second Clinical College of Guangzhou, University of Chinese Medicine, Guangzhou, <510006>, China.
Guangdong Provincial Engineering Research Center for Modernization of TCM, NMPA Key Laboratory for Quality Evaluation of TCM, Jinan University, Guangzhou, 510632, P. R. China.
Chem Biodivers. 2023 Mar;20(3):e202201110. doi: 10.1002/cbdv.202201110. Epub 2023 Mar 6.
Hepatic fibrosis is a global health problem, which currently has no FDA approved antifibrotic therapy yet. This study aimed to explore the mechanism of Hovenia genus in the treatment of hepatic fibrosis by an integrative strategy combining network pharmacology analysis, molecular docking, transcriptomics and experimental validation. The traditional Chinese medicine systems pharmacology (TCMSP) database and literatures were used to collect the components of Hovenia genus. Public databases including GeneCards, TTD, PharmGkb were used to acquire the putative targets. The GO and KEGG analysis were applied to explore the underlying mechanisms. Furthermore, The TGF-β1 induced hepatic stellate cells (HSCs) model were performed to evaluate the anti-hepatic fibrosis activity of Hovenia genus. The RT-qPCR, Western blotting and flow cytometry experiments were used to validate the anti-hepatic fibrosis mechanisms of Hovenianin A. The KEGG analysis of network pharmacology and transcriptomics revealed that the core targets mainly enriched in PI3K-Akt signaling pathways. The cell screening results indicated flavonoids were the main active ingredients of Hovenia. Hovenianin A, a bioactive bisflavonol, was validated to promote the apoptosis of HSCs by inhibiting PI3K-Akt pathway. Molecular docking further corroborated the binding sites between Hovenianin A and AKT1. In summary, Hovenia may have therapeutic effects on liver fibrosis by modulating the PI3K-Akt apoptosis pathway. Our findings may facilitate the development of Hovenia genus, which could help to treat liver fibrosis in the future.
肝纤维化是一个全球性的健康问题，目前还没有获得美国食品和药物管理局（FDA）批准的抗纤维化治疗方法。本研究旨在通过整合网络药理学分析、分子对接、转录组学和实验验证的策略，探索枳属治疗肝纤维化的机制。利用中药系统药理学（TCMSP）数据库和文献收集枳属的成分。利用 GeneCards、TTD、PharmGkb 等公共数据库获取假定靶点。应用 GO 和 KEGG 分析探讨潜在机制。此外，还进行了 TGF-β1 诱导的肝星状细胞（HSCs）模型，以评估枳属的抗肝纤维化活性。采用 RT-qPCR、Western blot 和流式细胞术实验验证了枳椇素 A 的抗肝纤维化机制。网络药理学和转录组学的 KEGG 分析表明，核心靶点主要富集在 PI3K-Akt 信号通路中。细胞筛选结果表明，黄酮类化合物是枳属的主要活性成分。枳椇素 A 是一种生物活性双黄酮醇，通过抑制 PI3K-Akt 通路被验证可促进 HSCs 的凋亡。分子对接进一步证实了枳椇素 A 与 AKT1 之间的结合位点。综上所述，枳属可能通过调节 PI3K-Akt 凋亡通路对肝纤维化发挥治疗作用。我们的发现可能有助于枳属的开发，有助于未来治疗肝纤维化。
