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

Pang, J; Al-Ani, AH; Patel, KM; Zhou, Y; Young, SN; Chen, J; Kong, I; Barrios, M; Rickard, JA; Chen, S; Ma, X; Shojaee, F; Kim, SB; Foroughi, S; Cawthorne, W; Jacobsen, AV; Jois, A; Weir, AL; Whitehead, LW; Rajasekhar, P; Horne, CR; Lyu, R; Mather, LJ; Yip, RKH; Tsui, E; Azeez, I; Tan, T; Liang, W; Sivanesan, S; Metz, A; Patwardhan, A; Shea, N; Iyngkaran, G; Schneider, D; Elford, AT; Beattie, W; Macrae, F; Liccardi, G; Walczak, H; Zhang, Y; Sieber, OM; Spelman, T; Giulino-Roth, L; Christie, M; Chen, Y; Rogers, KL; Bowden, R; Nicholson, SE; Lawlor, KE; Hawkins, ED; Christensen, B; Samson, AL; Vince, JE; Murphy, JM

Author(s): Pang, J; Al-Ani, AH; Patel, KM; Zhou, Y; Young, SN; Chen, J; Kong, I; Barrios, M; Rickard, JA; Chen, S; Ma, X; Shojaee, F; Kim, SB; Foroughi, S; Cawthorne, W; Jacobsen, AV; Jois, A; Weir, AL; Whitehead, LW; Rajasekhar, P; Horne, CR; Lyu, R; Mather, LJ; Yip, RKH; Tsui, E; Azeez, I; Tan, T; Liang, W; Sivanesan, S; Metz, A; Patwardhan, A; Shea, N; Iyngkaran, G; Schneider, D; Elford, AT; Beattie, W; Macrae, F; Liccardi, G; Walczak, H; Zhang, Y; Sieber, OM; Spelman, T; Giulino-Roth, L; Christie, M; Chen, Y; Rogers, KL; Bowden, R; Nicholson, SE; Lawlor, KE; Hawkins, ED; Christensen, B; Samson, AL; Vince, JE; Murphy, JM;
Details: Publication Year 2026-08-27,Volume 393,Issue #6814,Page eaeh7112
Journal Title: Science
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.
Publisher: AAAS
Keywords: Humans; *Apoptosis; Animals; Signal Transduction; Nitric Oxide Synthase Type II/metabolism; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics; *Intestinal Mucosa/pathology; Apoptosis Regulatory Proteins/metabolism/genetics; Mice; Macrophages/immunology; *Necroptosis/genetics; *Inflammatory Bowel Diseases/pathology; Mitochondria/metabolism; *Epithelial Cells/pathology; Proto-Oncogene Proteins/metabolism; Tumor Suppressor Proteins
Research Division(s): Inflammation; New Medicines and Diagnostics; Bioinformatics and Computational Biology; Blood Cells and Blood Cancer; Infection and Global Health; Personalised Oncology; Clinical Discovery and Translation
PubMed ID: 42658927
Publisher's Version: https://doi.org/10.1126/science.aeh7112
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-09-07 09:09:48

Last Modified: 2026-09-07 09:09:58