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Data from: A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease

Kong, Isabella1; Hawkins, Edwin2; Rogers, Kelly2; Yip, Ka Ho Raymond2; Giulino-Roth, Lisa1; Cawthorne, Wayne2; Sieber, Oliver2; Jacobsen, Annette2; Horne, Christopher2; Young, Samuel2; Chen, Yunshun2; Whitehead, Lachlan2; Liang, Weiwei3; Chen, Siqi2; Jois, Asha2; Tan, Tao2; Sivanesan, Suresh4; Shea, Natalie4; Schneider, Daniel4; Elford, Alexander4; Spelman, Tim2; Iyngkaran, Guru4; Foroughi, Siavash2; Nicholson, Sandra2; Barrios, Marilou2; Ma, Xiuquan2; Lawlor, Kate2; Vince, James2; Murphy, James2; Shojaee, Farzaneh2; Bowden, Rory2; Metz, Andrew4; Weir, Ashley2; Abdul Azeez, Imadh2; Al-Ani, Aysha2; Rajasekhar, Pradeep2; Liccardi, Gianmaria5; Christensen, Britt2; Beattie, William6; Patwardhan, Ashwin4; Walczak, Henning5; Macrae, Finlay4; Kim, Seong-Beom7; Patel, Komal2; Pang, Jiyi2; Mather, Lucy2; Christie, Michael2; Rickard, James2; Chen, Jinjin2; Zhang, Yuxia3; Lyu, Ruqian2; Samson, Andre2; Zhou, Yunzhuo2

Published Sep 30, 2026 on Dryad. https://doi.org/10.5061/dryad.wm37pvn39

Data files

Sep 30, 2026 version files 2.12 GB

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Abstract

Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, we identify excess epithelial cell death as an underlying feature of IBD that arises in both patients in remission and on advanced therapy. Mechanistically, nascent inflammation skews epithelial cells into a macrophage-like transcriptional state that promotes RIPK1-independent necroptotic signaling, then triggers iNOS-assisted mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. These findings reveal aberrant epithelial cell death signaling as a hallmark of IBD that occurs early in mucosal lesion development, persists despite current therapeutic strategies, and predicts clinical relapse.