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Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, we identified aberrant epithelial cell death signaling as an underlying feature of IBD that arises in patients in remission and on advanced therapy. Mechanistically, nascent inflammation skewed epithelial cells into an M1-macrophage\u2013like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase\u2013assisted mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. Thus, aberrant epithelial cell death signaling represents a hallmark of IBD that occurs early in mucosal lesion development, persists despite current therapeutic strategies, and predicts clinical relapse.<\/jats:p>","DOI":"10.1126\/science.aeh7112","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T18:01:42Z","timestamp":1787853702000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease"],"prefix":"10.1126","volume":"393","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1680-7274","authenticated-orcid":true,"given":"Jiyi","family":"Pang","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia."},{"name":"University of Melbourne, Parkville, VIC, 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