Elucidation of the protective effect of schisandrin C originating from Schisandra chinensis (Turcz.) Baill. against indomethacin-induced intestinal injury by combining network pharmacology, molecular docking, and experimental validation

Abstract Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin, has severe adverse effects on the gastrointestinal system. Schisandra chinensis (Turcz.) Baill., an herbal medicine used to treat several gastrointestinal diseases, might effectively reduce the adverse effects of indomethacin. This study aimed to elucidate the main bioactive compound from S. chinensis and its molecular mechanism for protection against indomethacin-induced intestinal injury. Network pharmacology, molecular docking, and molecular dynamics were performed to elucidate the key compounds of S. chinensis , their relevant targets, and potential molecular mechanisms via various databases, including the TCMSP, SwissTargetPrediction, TargetNet, STRING, and DAVID databases. The protective effect of the key compound and its molecular mechanism were validated in intestinal cells and Caenorhabditis elegans models. Network pharmacology analysis demonstrated that schisandrin C (SCHC) is the active ingredient of S. chinensis and protects against indomethacin-induced intestinal injury. Computational analysis revealed that AKT1, PIK3CA, RELA, EGFR, and GSK3B are potential targets of SCHC. In vitro experiments confirmed that SCHC prevents apoptotic cell death and intestinal permeability dysfunction by modulating the AKT/GSK-3β pathway and tight junction protein expression. Furthermore, SCHC ameliorated the intestinal atrophy induced by indomethacin and increased the intestinal lysosomal level in C. elegans , while its protective effect was abolished in age-1 and akt-1 , 2 mutants, indicating the involvement of the PI3K/AKT pathway. In summary, this study demonstrated that SCHC could be a potential candidate for reversing the side effects of indomethacin in the intestinal tract by combining network pharmacology, molecular docking, and experimental validation.