Identification of CD40 as the target of artemisinin via targeted degradomics for ulcerative colitis.

Current drugs for ulcerative colitis often face challenges such as significant side effects, high costs, and tendency to induce drug resistance. Repurposing existing drugs is a promising approach that builds on their known safety and efficacy profiles. Artemisinin (Art), a first-line antimalarial agent, shows anti-inflammatory activity. Malaria infection is frequently accompanied by severe intestinal inflammation and barrier disruption, pathological features that share similarities with ulcerative colitis. However, Art's precise anti-inflammatory mechanism and its therapeutic efficacy in ulcerative colitis remain unclear. In this study, using a DSS-induced ulcerative colitis mouse model, we confirmed that Art significantly ameliorates colitis symptoms and restores intestinal barrier function. Mechanistically, we used PROTAC-based targeted degradomics and identified the immunomodulatory protein CD40 as a candidate target of Art. Art treatment was associated with reduced CD40-TRAF6 interaction, suppression of downstream NF-κB and MAPK inflammatory signaling, and decreased release of inflammatory cytokines. This study provides a novel drug candidate and mechanistic foundation for the application of Art in the treatment of ulcerative colitis.