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

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 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-like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase-assisted 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.

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Publication Details

Journal
Science
Published
2026-08-27
DOI
https://doi.org/10.1126/science.aeh7112
Citations
6
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
3.17

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article

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

Lisa Giulino‐Roth, I. A. Azeez, Tim Spelman, Suresh Sivanesan et al.
6 citations
Science
Phagocytosis and Immune Regulation
3.17
article

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

Lisa Giulino‐Roth, I. A. Azeez, Tim Spelman, Suresh Sivanesan, Lachlan Whitehead, Oliver M. Sieber, Guru Iyngkaran, Britt Christensen, James M. Murphy, Wayne Cawthorne, James E. Vince, Yunzhuo Zhou, Sandra E. Nicholson, Ashley Weir, Tao Tan, Asha Jois, Annette V. Jacobsen, Samuel N. Young, Siavash Foroughi, Edwin D. Hawkins, Alexander T. Elford, Weiwei Liang, Xiuquan Ma, Kate E. Lawlor, Farzaneh‐Sadat Rezazadeh‐Shojaee, Marilou Barrios, Jiyi Pang, Gianmaria Liccardi, Pradeep Rajasekhar, Kelly L. Rogers, Michael Christie, Yunshun Chen, Rory Bowden, Raymond K. H. Yip, Natalie Shea, Aysha Al‐Ani, André L. Samson, Henning Walczak, Ruqian Lyu, Komal Patel, Ellen Tsui, Siqi Chen, Jinjin Chen, Yuxia Zhang, Daniel Schneider, Lucy J. Mather, Andrew Metz, William Beattie, Christopher R. Horne, James A. Rickard, Ash Patwardhan, Seong-Beom Kim, Isabella Kong, Finlay Macrae
article en
6 citations

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 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-like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase-assisted 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.

ScienceVol. 393(6814)
The Royal Melbourne Hospital (AU), Royal Children's Hospital (AU), The University of Melbourne (AU), University of Cologne (DE), Walter and Eliza Hall Institute of Medical Research (AU), Nankai University (CN), Cornell University (US), Parks Victoria (AU), Hudson Institute of Medical Research (AU), Zhengzhou University (CN), Guangzhou Women and Children Medical Center (CN), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Third Affiliated Hospital of Zhengzhou University (CN), CRUK Lung Cancer Centre of Excellence (GB), CSIRO Manufacturing (AU), University College London (GB), Ulsan National Institute of Science and Technology (KR), Monash University (AU), Guangzhou Medical University (CN)
Wellcome Trust, Medical Research Council, Australian Research Council, National Health and Medical Research Council
Openalex Percentile: Top 16%
Phagocytosis and Immune Regulation
3.17
DOISourceOpenAlex
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