ArticleGastro hep advances2026
Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs for Permeability Barrier Healing.
Article in Gastro hep advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
6 authors.
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Abstract
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, 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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