Targeting the AGE-RAGE/NF-κB Pathway: An Integrative Study Decoding the Anti-Colitis Effect of Five-Flavor Sophora...

Background: The Five-flavor Sophora Flavescens Enteric-coated Capsule (FSEC) is widely used to treat ulcerative colitis (UC), yet its underlying molecular mechanisms remain incompletely understood. This study aimed to systematically elucidate the therapeutic mechanisms and clinical value of FSEC by integrating network pharmacology, experimental validation, and clinical data. Methods: A multi-tiered methodological framework was implemented. First, network pharmacology analysis identified potential molecular targets and signaling pathways associated with FSEC in UC. These predictions, including the core targets and the AGE-RAGE/NF-κB signaling pathway, were subsequently validated in a dextran sulfate sodium-induced mouse colitis model in vivo and a lipopolysaccharide-stimulated RAW264.7 macrophage inflammation model in vitro. Finally, a single-center retrospective cohort study of 90 patients evaluated the efficacy and safety of FSEC as monotherapy and in combination with Mesalazine. Results: Network pharmacology identified 12 core targets and predicted the AGE-RAGE/NF-κB pathway as a key mechanism. Experimental validation demonstrated that FSEC inhibits this pathway. Both in vivo and in vitro studies consistently showed that FSEC downregulates RAGE expression and NF-κB p65 phosphorylation, reducing the production of key inflammatory mediators and thereby alleviating intestinal inflammation. Clinically, FSEC monotherapy achieved efficacy comparable to that of Mesalazine, and combination therapy was associated with higher clinical remission and mucosal healing rates, with a favorable safety profile. Conclusions: This comprehensive multi-omics investigation provides integrated evidence that FSEC exerts anti-inflammatory effects, associated with inhibition of the AGE-RAGE/NF-κB pathway. The observed synergy between FSEC and Mesalazine suggests the potential of an integrated therapeutic approach for UC.