Mechanisms Underlying the Protective Effects of Obeticholic Acid-activated FXR in Valproic Acid-induced Hepatotoxicity via Network Pharmacology, Molecular Docking and Molecular Dynamics Simulations

Abstract This study aims to comprehensively investigate the underlying mechanisms of farnesoid X receptor (FXR) activation by obeticholic acid (OCA) in the treatment of VPA-induced hepatotoxicity. Network pharmacology was performed to identified the potential targets and pathways underlying the amelioration of VPA-induced hepatotoxicity by OCA. The identified pathways were validated through GEO data analysis, and the interactions between OCA and potential targets were predicted using molecular docking as well as molecular dynamics simulations. A total of 462 targets associated with VPA-induced hepatotoxicity and 288 targets of OCA were identified, with 81 overlapping targets between VPA-induced hepatotoxicity and OCA. KEGG pathway and GO enrichment analysis indicated that the effect of OCA on VPA-induced hepatotoxicity primarily involved lipid metabolism, as well as oxidative stress and inflammation. The results of GEO data analysis, molecular docking and molecular dynamics simulations revealed a close association between bile secretion, PPAR signaling pathway, and the treatment of VPA-induced hepatotoxicity by OCA. Our findings revealed that OCA exhibits potential therapeutic efficacy against VPA-induced hepatotoxicity through multiple targets and pathways, thereby highlighting the therapeutic potential of FXR as a target for the treatment of VPA-induced hepatotoxicity.