Regulation of Inducible Nitric Oxide Synthase (NOS2) Expression in Healthy and Inflamed Bowel: A Narrative Review

Crohn’s disease and ulcerative colitis, the principal forms of inflammatory bowel disease (IBD), are chronic inflammatory disorders characterized by recurrent intestinal injury, impaired mucosal healing, and substantial disease burden. Despite significant therapeutic advances, many patients fail to achieve sustained remission, highlighting the need for a better understanding of the molecular mechanisms driving intestinal inflammation. Nitric oxide (NO) is a key regulator of intestinal homeostasis, influencing epithelial barrier integrity, vascular function, host defense, and immune responses. In IBD, dysregulated production of NO, largely attributable to inducible nitric oxide synthase (NOS2), has been associated with both protective and pathogenic effects. Accumulating evidence indicates that the biological consequences of NOS2 activation depend on the cellular source of NO, local microenvironmental signals, and disease context. This review summarizes current knowledge on the transcriptional, epigenetic, post-transcriptional, translational, and post-translational mechanisms regulating NOS2 expression and activity in the intestine. Particular emphasis is placed on cell-specific regulation in epithelial, stromal, endothelial, neural, and immune-cell populations, as well as emerging insights from single-cell and spatial transcriptomic studies. Collectively, available evidence supports a context-dependent role for NOS2 in IBD and highlights the importance of cell-specific approaches for future biomarker development and therapeutic targeting.