Abstract

This study aims to identify the most primary hepatoprotective compound from Hypericum japonicum and elucidate its underlying mechanisms of liver protection. This study screened 15 compounds from Hypericum japonicum against D-GalN-induced AML12 cell injury, identifying TAX (Compound 8, taxifolin 7-rhamnoside) as the most hepatoprotective. This study indicates that TAX reduced AST, ALT, and MDA levels, while enhancing SOD and GSH levels in D-GalN-induced AML12 and LPS/D-GalN -induced liver. In addition, TAX attenuated LPS/D-GalN-induced hepatic injury by lowering inflammatory infiltration and pro-inflammatory cytokines (TNF-α, IL-6 and NO) levels. Network pharmacology analysis revealed common targets between TAX and drug-induced liver injury, forming a protein-protein interaction (PPI) network. Functional enrichment (GO/KEGG) and molecular docking indicated strong binding affinity between TAX and AKT1, confirmed by molecular dynamics simulations. Western blot analyses that TAX ameliorated inflammation and oxidative stress through down-regulating the AKT/NF-κB pathways and up-regulating Nrf2/HO-1 pathways in vivo, TAX inhibited apoptosis via up-regulating Bcl-2 and down-regulating Bax in vitro. Collectively, this study demonstrates that TAX ameliorates LPS/D-GalN-induced ALI by attenuating hepatocyte apoptosis, inflammatory responses, and oxidative stress.