Nrf2 as a Molecular Guardian of Redox Balance and Barrier Integrity in IBD
Bojan Stojanović, Ivana Milivojcević Bevc, Milica Dimitrijevic Stojanovic, Bojana Stojanović, Marina Jovanović, Snežana Lazarević, Bojan Milošević, Ivan Radosavljević, Danijela Tasic-Uros, Nenad Marković, Đorđe Todorovic, Irfan Ćorović, Filip Milutinović, Damnjan Pantic, Mladen Maksić, Snežana Lukić
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, represents a chronic inflammatory condition of the gastrointestinal tract characterized by immune dysregulation, oxidative stress, and impaired epithelial barrier function. Among the complex molecular networks involved, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a central regulator of redox balance, anti-inflammatory signaling, and mucosal homeostasis. This review provides a comprehensive overview of the pathogenic role of oxidative stress in IBD, detailing the sources and consequences of reactive oxygen species (ROS) accumulation, and the mechanisms by which Nrf2 activation counters these effects. We discuss the dual regulation of Nrf2 through Keap1-dependent and Keap1-independent pathways, its influence on epithelial integrity, immune cell polarization, microbiota composition, and its paradoxical role in IBD-associated tumorigenesis and fibrosis. Furthermore, we highlight emerging therapeutic strategies aimed at modulating Nrf2 activity via pharmacologic agents, dietary phytochemicals, and probiotics. Taken together, these insights position Nrf2 as a pivotal therapeutic target in IBD, offering new avenues for restoring epithelial resilience, mitigating chronic inflammation, and improving clinical outcomes.