IMMUNOPROTEASOME INHIBITION AS AN EMERGING THERAPEUTIC STRATEGY IN INFLAMMATORY BOWEL DISEASE
Main Article Content
Keywords
Inflammatory Bowel Disease, Proteasome Inhibition, NF-κB, Immunoproteasome, Targeted Therapy, Intestinal Inflammation
Abstract
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.
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4. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389:1756–70. doi: 10.1016/S0140-6736(16)32126-2.
5. Ocansey DKW, Zhang L, Wang Y, Yan Y, Qian H, Zhang X, et al. Exosome-mediated effects and applications in inflammatory bowel disease. Biol Rev Camb Philos Soc. 2020;95:1287–307. doi: 10.1111/brv.12608.
6. Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: a comprehensive review. Front Med (Lausanne). 2021;8:765474. doi: 10.3389/fmed.2021.765474.
7. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med. 2013;369:754–62. doi: 10.1056/NEJMct1209614.
8. Ben-Horin S, Kopylov U, Chowers Y. Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmun Rev. 2014;13:24–30. doi: 10.1016/j.autrev.2013.06.002.
9. Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, et al. Ameliorating effects of bortezomib, a proteasome inhibitor, on development of dextran sulfate sodium-induced murine colitis. J Clin Biochem Nutr. 2018;63(3):217–23. doi: 10.3164/jcbn.18-42.
10. Scalavino V, Piccinno E, Valentini AM, Mastronardi M, Armentano R, Giannelli G, et al. A novel mechanism of immunoproteasome regulation via mir-369-3p in intestinal inflammatory response. Int J Mol Sci. 2022;23(22):13771. doi: 10.3390/ijms232213771.
11. Basler M, Lindström M, LaStant J, Bradshaw JM, Owens TD, Schmidt C, et al. Co-inhibition of immunoproteasome subunits lmp2 and lmp7 is required to block autoimmunity. EMBO Rep. 2018;19(12). doi: 10.15252/embr.201846512.
12. Aguilera M, Melgar S. Microbial Neuro-Immune Interactions and the Pathophysiology of IBD. In: InTech; 2016. doi: 10.5772/64832.
13. Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. 2014;20(1):91–9. doi: 10.3748/wjg.v20.i1.91.
14. Xu XR, Liu CQ, Feng BS, Liu ZJ. Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2014;20(12):3255–64. doi: 10.3748/wjg.v20.i12.3255.
15. Gomez-Bris R, Saez A, Herrero-Fernandez B, Rius C, Sanchez-Martinez H, Gonzalez-Granado JM. CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease. Int J Mol Sci. 2023;24(3):2696. doi: 10.3390/ijms24032696.
16. Cominelli F, Arseneau KO, Rodriguez-Palacios A, Pizarro TT. Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn's Disease-Like Ileitis: What is the Right Model?. Cell Mol Gastroenterol Hepatol. 2017;4(1):19–32. doi: 10.1016/j.jcmgh.2017.02.010.
17. Du Y. Role of epigenetic modifications and aging in inflammatory bowel disease. Mol Ecol Funct Genomics. 2023;2(4). doi: 10.1002/mef2.63.
18. Ouahed JD. Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease. Front Immunol. 2022;13:1026511. doi: 10.3389/fimmu.2022.1026511.
19. Fakhoury M, Negrulj R, Mooranian A, Al-Salami H. Inflammatory bowel disease: clinical aspects and treatments. J Inflamm Res. 2014;7:113–20. doi: 10.2147/JIR.S65979.
20. Eichele DD, Kharbanda KK. Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis. World J Gastroenterol. 2017;23(33):6016–29. doi: 10.3748/wjg.v23.i33.6016.
21. Anbazhagan AN, Priyamvada S, Alrefai WA, Dudeja PK. Pathophysiology of IBD associated diarrhea. Tissue Barriers. 2018;6(2):e1463897. doi: 10.1080/21688370.2018.1463897.
22. Zheng M, Han R, Yuan Y, Xing Y, Zhang W, Sun Z, et al. The role of Akkermansia muciniphila in inflammatory bowel disease: Current knowledge and perspectives. Front Immunol. 2023;13:1089600. doi: 10.3389/fimmu.2022.1089600.
23. Tahir MH, Jamil HMA, Lodhi T, Mehdi M, Ali M, Ullah I. Effect of gut microbiome alteration in inflammatory bowel disease: Microbiome-based therapy for irritable bowel syndrome. Int J Health Sci. 2023;7(S1):1713–22. doi: 10.53730/ijhs.v7nS1.14405.
24. Van der Sloot KWJ, Weersma RK, Alizadeh BZ, Dijkstra G. Identification of Environmental Risk Factors Associated With the Development of Inflammatory Bowel Disease. J Crohns Colitis. 2020;14(12):1662–71. doi: 10.1093/ecco-jcc/jjaa114.
25. Mak JWY, Lo ATW, Ng SC. Early life factors, diet and microbiome, and risk of inflammatory bowel disease. J Can Assoc Gastroenterol. 2025;8(Suppl 2):S44–50. doi: 10.1093/jcag/gwae039.
26. El-Salhy M, Hausken T. The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). Neuropeptides. 2016;55:137–44. doi: 10.1016/j.npep.2015.09.005.
27. Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med. 2017;282(1):46–63. doi: 10.1111/joim.12611.
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Sep 29, 2025
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Krishna Thakkar, Sonika Maheshwari, Dr. Nishkruti R. Mehta, & Dr. Pragnesh Patani. (2025). IMMUNOPROTEASOME INHIBITION AS AN EMERGING THERAPEUTIC STRATEGY IN INFLAMMATORY BOWEL DISEASE. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1138-1152. https://doi.org/10.53555/b90dcw55
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Author Biographies
Krishna Thakkar
Student, Khyati College of Pharmacy, Palodiya, Ahmedabad
Sonika Maheshwari
Assistant Professor, Department of Pharmacology, Khyati College of Pharmacy, Palodiya, Ahmedabad
Dr. Nishkruti R. Mehta
HOD, Department of Pharmacology, Khyati College of Pharmacy, Plodiya, Ahmedabad
Dr. Pragnesh Patani
Principal, Khyati College of Pharmacy, Palodiya, Ahmedabad
How to Cite
Krishna Thakkar, Sonika Maheshwari, Dr. Nishkruti R. Mehta, & Dr. Pragnesh Patani. (2025). IMMUNOPROTEASOME INHIBITION AS AN EMERGING THERAPEUTIC STRATEGY IN INFLAMMATORY BOWEL DISEASE. Journal of Population Therapeutics and Clinical Pharmacology, 32(8), 1138-1152. https://doi.org/10.53555/b90dcw55