Abstract Background Tirzepatide, a drug initially developed for the treatment of type 2 diabetes, has demonstrated metabolic and anti-inflammatory effects, with excellent tolerability. Therefore, its use could potentially be extended to gastrointestinal conditions, including inflammatory bowel disease (IBD)1. Additionally, epidemiological studies suggest that the use of GLP-1 receptor agonists is associated with a reduced risk of developing colorectal cancer (CRC)2. However, the effects of dual agonists, such as Tirzepatide, in relevant chronic models of colitis and CAC have not yet been evaluated. Methods Winnie mice with chronic colitis and CAC3 were treated with Tirzepatide (30 nmol/kg) once weekly for 8 weeks or with the vehicle (n = 12). The severity of colitis and tumor burden was analyzed by stereomicroscopy and histological scoring by a blinded pathologist. RT-qPCR and Western blot were used to measure the expression of cytokine and tumor marker genes. Results Stereomicroscopic analysis revealed fewer and smaller polypoid lesions, a decreased tumor burden (p 0.001), and improved weight stability compared to progressive weight loss in Tirzepatide-treated mice versus controls (p 0.02). Histologic analysis revealed improved crypt architecture, fewer dysplastic regions, and a significant reduction in inflammation and dysplasia (p 0.001). At the molecular level, Tirzepatide downregulates the expression of colon cancer-associated genes Myc, Cdkn1a, and Lgr5 (p 0.01). Immunoblotting of colonic tissues indicates reduced protein levels of phosphorylated AKT, phosphorylated PFK2, and Cyclin D1, reflecting suppression of pro-survival and proliferative signaling pathways. A global reduction in colonic inflammation following Tirzepatide was also observed, indicated by decreased expression of the proinflammatory cytokines il-6, il-1β, and tnf, and further supported by significantly lower stool lipocalin-2 levels (p 0.002). Conclusion Our results demonstrate that Tirzepadite significantly lessened the severity of colitis and reduced tumor burden in Winnie mice with colitis and CAC. Furthermore, our data indicate a direct effect of Tirzepatide, related to its ability to regulate inflammatory pathways and induce apoptosis in cancer cells, rather than being solely a result of weight loss. This supports a mechanism where Tirzepatide disrupts both metabolic and mitogenic reprogramming in colonic epithelial cells. These findings imply that Tirzepatide could be a promising candidate for linking metabolic and immune pathways in the treatment of inflammation-related colon cancer. As research progresses, repositioning Tirzepatide for patients with these complex conditions may transform treatment strategies for IBD. References: 1.Wong CK, Drucker DJ. Antiinflammatory actions of glucagon-like peptide-1-based therapies beyond metabolic benefits. J Clin Invest. 2025;135:e194751. doi: 10.1172/JCI1947512. 2.Wang L, Xu R, Kaelber DC, et al. Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers 3.Verna G, De Santis S, Islam BN, et al. A missense mutation in Muc2 promotes gut microbiome- and metabolome-dependent colitis-associated tumorigenesis. J Clin Invest. 2025;e196712. doi: 10.1172/JCI196712 Conflict of interest: Islam, Bianca: No conflict Nguyen-Gomez, Adrian: No conflict Williams, Kristina: No conflict Curry, Kim: No conflict of interest Khandekar, Neha: No conflict of interest Chieppa, Marcello: No conflict of interest Xin, Wei: No conflict of interest Pizarro, Theresa: No conflict of interest Wang, Rui: No conflict of interest Prof. Dr. Cominelli, Fabio: No conflict of interest
Islam et al. (Thu,) studied this question.