Intestinal subepithelial myofibroblasts in inflammatory bowel disease: fibroblast heterogeneity, fibrosis, and therapeutic targeting

Intestinal fibrosis is one of the most serious complications of inflammatory bowel disease (IBD), often leading to bowel strictures, impaired function, and need for surgery. Subepithelial myofibroblasts of the intestine (ISEMFs) are key regulators of mucosal integrity, tissue repair, and immune responses. However, during chronic inflammation, ISEMFs can be pathologically activated, leading to excessive extracellular matrix deposition and progressive fibrosis. The article addresses the physiological and pathological role of ISEMFs in IBD, including their functions in maintaining epithelial integrity and supporting tissue repair. It examines the mechanisms of ISEMF activation during chronic inflammation, emphasizing signaling pathways such as TGF-β/Smad, JAK/STAT, and Wnt/β-catenin. Recent advances in single-cell and spatial analyses have revealed significant fibroblast heterogeneity and identified pathogenic subsets associated with fibrostenotic disease. The article summarizes current and emerging therapeutic strategies targeting the stroma, including antifibrotic agents and biomarker-guided precision approaches.