IMMUNOPROTEASOME INHIBITION AS AN EMERGING THERAPEUTIC STRATEGY IN INFLAMMATORY BOWEL DISEASE

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a chronic, relapsing disorder of the gastrointestinal tract with a rapidly rising global prevalence. Despite significant advances in immunomodulators, biologics, and small-molecule therapies, current treatments remain constrained by limited response rates, secondary loss of efficacy, and adverse effects. Increasing evidence implicates genetic susceptibility, impaired mucosal barrier function, gut microbiota dysbiosis, and immune dysregulation—particularly aberrant nuclear factor kappa B (NF-κB) activation—in driving chronic intestinal inflammation. The proteasome, a key regulator of intracellular protein degradation, directly controls NF-κB signaling and other inflammatory pathways. Recent preclinical studies demonstrate that proteasome inhibition, especially selective targeting of the immunoproteasome, effectively suppresses pro-inflammatory cytokine expression, attenuates colitis severity, and promotes mucosal healing, while offering greater specificity and reduced systemic toxicity compared to conventional inhibitors. However, challenges such as systemic adverse effects, epithelial barrier disruption, and limited clinical validation remain significant barriers to translation. Emerging strategies, including nanoparticle-mediated targeted delivery, subunit-specific inhibitors, and rational combination with existing immunomodulators or biologics, are under active exploration to optimize efficacy and safety. Furthermore, biomarker-guided patient stratification and long-term safety studies are essential to establish therapeutic viability. Collectively, proteasome inhibition represents a promising and mechanistically rational approach to IBD management, with the potential to overcome limitations of existing therapies. Advancing selective, locally targeted, and clinically validated inhibitors could position immunoproteasome modulation as a transformative strategy in refractory IBD treatment.