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A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic condition caused by imbalanced cytokine signaling, maladaptive immunity, dysbiosis and intestinal barrier dysfunction. Patients with IBD receive therapy to correct these imbalances and achieve remission. However, most patients will relapse, suggesting that other pathological mechanisms persist during remission. Here, we show that excess epithelial cell death is an underlying feature of IBD that arises in patients in remission and on gold-standard therapy. Mechanistically, nascent inflammation reprograms epithelial cells into a macrophage-like-state that promotes sublethal ZBP1-dependent RIPK1-independent necroptotic signaling, then triggers iNOS-mediated apoptosis of absorptive epithelia and PUMA-mediated intestinal stem cell death. These findings unveil aberrant epithelial cell death signaling as a hallmark of IBD that occurs early in inflammation development and is persistent despite current therapeutic approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282165 | GEO | 2026/09/03

REPOSITORIES: GEO

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