Bioactive components from Pericarpium Citri Reticulatae 'Chachi' alleviates ulcerative colitis by PI3K/AKT signaling pathway: Network pharmacology, molecular docking and experimental verification.

Citri Reticulatae Pericarpium 'Chachi' (PCRC), a traditional Chinese medicinal herb with dual applications in medicine and food, has demonstrated significant efficacy in treating gastrointestinal disorders. Especially, researches have highlighting PCRC's therapeutic effects on ulcerative colitis (UC). However, bioactive ingredients of PCRC and their molecular mechanisms are still unclear. This study aims to identify the active ingredients of PCRC for UC treatment, explore the molecular mechanisms by network pharmacology and molecular docking, and experimentally verify the therapeutic effects and mechanisms. Firstly, PCRC exhibited significant anti-inflammatory and antioxidant properties, indicating its potential as a promising candidate for UC treatment. Subsequently, a total of 40 components were identified in PCRC using HPLC-MS. Through network pharmacology, molecular docking, and in vitro experiments evaluating the release of NO and inflammatory factors, isosinensetin (ISS) was identified as a leading candidate for the treatment of UC. In UC mouse models, ISS significantly alleviated UC symptoms, mitigated oxidative stress markers (MDA, GSH and SOD), reduced inflammatory responses (IL-6, IL-1β and TNF-α), and enhanced the integrity of the intestinal epithelial barrier. According to KEGG and GO enrichment analyses and Western blot experiments, ISS exerts its therapeutic effects on UC by inhibiting the PI3K/AKT signaling pathway. Additionally, ISS administration was found to restore gut microbiota disturbances induced by UC. Overall, these findings indicate that ISS, derive from PCRC, may serve as a promising active ingredient for the treatment of UC and have significant implications for the practical application of PCRC.