Schisandrin C ameliorates indomethacin-induced intestinal injury: An integration study of network pharmacology, in vitro cells, and in vivo Caenorhabditis elegans

The long-term administration of indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), has been associated with severe gastrointestinal side effects by inducing inflammation, oxidative stress, and downregulating tight junction protein expression [ 1 ] [ 2 ]. Schisandra chinensis (Turcz.) Baill., an herbal medicine for treating gastrointestinal disorders, can potentially ameliorate these adverse effects [ 3 ]. This study aimed to discover the bioactive compound from S. chinensis and elucidate its mechanism of action underlying the protection against indomethacin. Network pharmacology analysis indicated that schisandrin C (SCHC), which exhibits the best drug-like properties, is the active ingredient of S. chinensis to protect against indomethacin-induced intestinal injury. The analysis revealed that SCHC might exhibit protection through various targets, such as AKT1, PIK3CA, GSK3B, RELA, and CASP9. Molecular docking and molecular dynamics simulation data indicated that SCHC has high binding affinities with GSK3B and PIK3CA. In vitro Caco-2 cell experiments indicated that SCHC reduced apoptotic cell death and intestinal inflammation and upregulated tight junction protein expression by modulating the AKT/GSK-3β signaling pathway. In addition, SCHC could effectively reduce intestinal atrophy and increase the intestinal lysosomal level in Caenorhabditis elegans induced by indomethacin. The protective effect of SCHC in C. elegans was also demonstrated to be associated with the PI3K/AKT signaling pathway through the loss in bioactivity of SCHC in mutant strains of age-1 , akt-1 , and akt-2 genes. In conclusion, by integrating computational predictions and experimental validation, this study suggests that SCHC can be a promising candidate for protecting against indomethacin-induced intestinal injury. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany