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Updated: Jun 9, 2026
An Intravital Microscopy-Based Approach to Assess Intestinal Permeability and Epithelial Cell Shedding Performance
Published on: December 3, 2020
Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs
Debasish Halder1, Ritwika Biswas Lanford1, Amin Esmaeilniakooshkghazi1
1Department of Biology and Biochemistry, The University of Houston, Houston, Texas.
Background And Aims:
Intestinal permeability dysfunction is a central pathogenic driver of Crohn's disease (CD), fueling microbial translocation, chronic inflammation, and progressive tissue injury. While current therapies suppress inflammation, none directly restore epithelial barrier function. Importantly, in patients with CD, epithelial barrier healing rather than mucosal healing is associated with long-term remission and a reduced risk of disease complications. Yet permeability barrier healing remains an unaddressed therapeutic target in CD. Here, we investigated whether pharmacologic inhibition of the integrated stress response (ISR) and RIPK3-mediated necroptosis, 2 convergent pathways of epithelial injury, can promote epithelial viability, regeneration, and barrier integrity in CD.
Methods:
We employed villin-1/gelsolin double knockout mice with epithelial-intrinsic ISR activation, Tnf ΔARE/+ mice with chronic inflammation, and CD patient-derived enteroids (PDEs). Animals and PDE were treated with integrated stress response inhibitor, RIPK3 inhibitor necrostatin-1, or US Food and Drug Administration-approved cancer drugs pazopanib and ponatinib, repurposed as potent RIPK3 inhibitors. Epithelial survival, regenerative growth (enteroid formation, budding), and barrier function (transepithelial electrical resistance) were assessed.
Results:
Chronic ISR activation and necroptosis were prominent in both murine models and CD PDEs, causing epithelial death, Paneth cell expansion, impaired enteroid survival, and regenerative failure. Pharmacologic inhibition with integrated stress response inhibitor, necrostatin-1, pazopanib, or ponatinib restored villus architecture, reduced inflammation, enhanced epithelial survival and regeneration, and significantly improved transepithelial electrical resistance.
Conclusion:
ISR activation and RIPK3-mediated necroptosis converge to drive epithelial injury and barrier dysfunction in CD. Repurposing pazopanib and ponatinib offers a potentially translatable approach to restore barrier integrity in CD.
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