Hovenianin A Alleviates Hepatic Fibrosis by Inhibiting the PI3K/AKT Pathway in TGF-beta 1-Induced HSCs Based on Network Pharmacology and Transcriptomic Analysis

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-beta 1 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.