ABSTRACT: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, epithelial barrier dysfunction, and maladaptive stromal remodelling that can progress to fibrosis. Current therapies primarily target inflammatory pathways and rarely achieve durable remission or structural disease modification, highlighting a major unmet clinical need. Here, we evaluated the therapeutic potential of YUQ-A1007, an orally active, gut-enriched small-molecule aryl hydrocarbon receptor (AhR) agonist, across multiple translational models of colitis. The anti-inflammatory, barrier-restorative, and anti-fibrotic effects of YUQ-A1007 were assessed using in vitro cell systems, patient-derived colonic biopsies and organoids, permeability assays, and three murine colitis models. YUQ-A1007 partially activated AhR signalling, suppressed pro-inflammatory cytokine production, enhanced regulatory T cell differentiation, increased tight junction protein expression, and inhibited fibrotic gene programs. In vivo, oral YUQ-A1007 administration reduced disease severity, restored epithelial barrier integrity, and broadly downregulated inflammatory cytokines, chemokines, fibrosis-associated genes, pro-inflammatory mesenchymal stromal cell biomarkers, and matrix metalloproteinases. In ulcerative colitis patient-derived colonic explants, YUQ-A1007 dose-dependently reduced inflammatory mediator secretion while preserving barrier function. Collectively, these findings support further development of YUQ-A1007 as a gut-targeted AhR therapeutic for ulcerative colitis and broader inflammatory bowel disease.
