Exploration of Potential Core Targets for Acute Liver Injury Based on a Novel Network Pharmacology Strategy Integrating the Common Efficacy and Mechanisms of Active Monomers

Acute liver injury (ALI) is defined as rapidly progressing hepatic dysfunction or hepatocellular necrosis caused by drugs or chemicals, viral infection, or autoimmune diseases, among which drug-induced liver injury (DILI) is the major etiology. Numerous monomeric compounds have shown hepatoprotective effects in animal models; however, their therapeutic specificity is limited, and their clinical applicability remains restricted. This study moved beyond the single-compound paradigm and systematically identified key candidate hubs of ALI by integrating the shared efficacy and mechanisms of hepatoprotective monomers. Monomeric compounds with preclinically confirmed hepatoprotective effects were obtained from PubMed. Network pharmacology was used to identify overlapping targets between monomers and ALI. Transcriptomic datasets were analyzed to explore the differential expression of candidate targets. In vivo validation was conducted in C57BL/6 mice using APAP- and LPS/D-GalN-induced ALI models. Molecular docking and molecular dynamics (MD) simulations were conducted to predict compound-target interactions. A total of 186 active monomers and four hub genes (JUN, STAT3, ESR1, and CTNNB1) were identified. Across multiple GEO datasets, JUN was the only consistently upregulated gene. In vivo models confirmed robust activation of phosphorylated c-Jun. Docking and MD analysis indicated stable binding of Schisandrol A, Withaferin A, and Schizandrin to JUN. This integrated strategy revealed JUN as a key candidate molecular hub in ALI. This study not only provides new ideas for exploring the common mechanism of ALI but also offers clues for the development of JUN-targeted hepatoprotective agents.