Kaempferol-3-O-glucorhamnoside alleviates DSS-induced ulcerative colitis via the arginine-polyamine metabolism pathway.

Abstract

Ulcerative colitis (UC) is a chronic, relapsing condition with a rising global prevalence. At present, there is a lack of therapeutic strategies that provide both high efficacy and minimal adverse effects. Kaempferol-3-O-glucorhamnoside (KA), a natural compound derived from Thesium chinense Turcz., has demonstrated significant anti-inflammatory properties. Nevertheless, its therapeutic potential and the precise molecular mechanisms underlying its effects in UC remain unexplored. In this study, KA administration effectively ameliorated a dextran sulfate sodium (DSS)-induced murine model of UC, as indicated by the restoration of body weight, restoration of colon length, a decrease in the disease activity index (DAI), reduced levels of the pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-17, and increased expression of tight junction proteins Claudin-1, Occludin, and ZO-1. Integrated untargeted metabolomic and transcriptomic analyses revealed that the anti-inflammatory efficacy of KA is primarily mediated by the arginine and proline metabolism pathway, wherein KA enhances downstream polyamine production by modulating the Arg1/ODC/polyamine axis. Furthermore, molecular docking, molecular dynamics (MD) simulations, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays demonstrated that KA directly binds to Arg1, thereby stabilizing the target protein and inhibiting its degradation. Additionally, pharmacological blockade of Arg1 using the specific inhibitor CB-1158 dihydrochloride substantially attenuated the KA-mediated activation of this metabolic pathway. Overall, KA demonstrated significant alleviative effects against experimental UC, indicating that this compound may represent a promising therapeutic candidate for UC.