Dihydroartemisinin facilitates intestinal mucosal healing in inflammatory bowel disease by targeting 11βHSD-1 to reprogram macrophage metabolism.

Abstract

BACKGROUND: Mucosal healing is a major clinical challenge and a critical prognostic factor in inflammatory bowel disease (IBD). Achieving mucosal healing requires the functional reprogramming of macrophages to facilitate intestinal stem cells (ISCs)-mediated repair, a process impaired in IBD due to dysregulated macrophage activity. Dihydroartemisinin (DHA), a derivative of artemisinin, shows promise in treating IBD, but its therapeutic potential remains underexplored due to its common classification as an anti-inflammatory agent. PURPOSE: This study aims to evaluate the efficacy of DHA in promoting mucosal healing in IBD and to elucidate the underlying mechanisms of macrophage reprogramming, thereby expanding the therapeutic potential of DHA beyond its conventional anti-inflammatory actions. METHODS: The therapeutic efficacy of DHA and its underlying mechanisms were systematically investigated using a DSS-induced colitis mouse model, with a focus on the repair phase. Mucosal healing was assessed through comprehensive histopathological and functional evaluations. DHA's role in macrophage metabolic reprogramming was explored through transcriptomic and metabolic analyses, and its effect on epithelial regeneration was examined using macrophage-organoid co-cultures. A molecular target discovery approach, integrating Mendelian randomization, molecular docking, and direct binding assays, identified 11βHSD-1 as a molecular target of DHA, which was subsequently confirmed through genetic and pharmacological loss-of-function studies in macrophages. RESULTS: Our findings demonstrated that DHA significantly promoted mucosal healing in a DSS-induced colitis model during the repair phase, as evidenced by reduced disease activity scores, increased colon length, and decreased histological damage. DHA also facilitated the recovery of gut functions, including barrier integrity, absorption, secretion, and motility. Macrophages were found to be essential for therapeutic effects of DHA. Specifically, DHA reprogrammed macrophage metabolism from glycolysis to oxidative phosphorylation, inducing a pro-repair phenotype characterized by enhanced secretion of Relmα and Wnt3a, which promoted the proliferation and differentiation of intestinal organoids. Mechanistically, we found that DHA directly bound to and activated 11βHSD-1, a key metabolic regulator in macrophages. This activation triggered STAT3/6 signaling, establishing a positive feedback loop that reinforced metabolic remodeling and facilitated the release of repair-promoting factors. CONCLUSION: Our findings demonstrate that DHA promotes intestinal mucosal healing by reprogramming macrophage metabolism, thereby enhancing ISC proliferation and differentiation. These results provide new insights into the potential of DHA in reshaping immune homeostasis, offering promising therapeutic strategies for IBD.