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203,234 studies31 sourcesUpdated 13 min ago
Peer-reviewedCC BYScience

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

  • Jiyi Pang1,2,3,4,5,6
  • Aysha Al‐Ani7,8,1,2,9,10,3,4,11,5,6
  • Komal M. Patel1,4,5
  • Yunzhuo Zhou1,4,5
  • Samuel N. Young1,12,13
  • Jinjin Chen1,2,3,4,5,6
  • Isabella Y. Kong14,3,4,5,6
  • Marilou H. Barrios1,2,10,4,11,5
  • James A. Rickard8,1,15,3,4,5,16,6
  • Siqi Chen17,1,2,3,4,5,6
  • Xiuquan Ma1,2,3,4,5,6
  • Farzaneh‐Sadat Rezazadeh‐Shojaee1,2,3,4,5,6
42 more authors
  • Seong-Beom Kim18,3,4,19,5,6
  • Siavash Foroughi1,2,3,4,5,6
  • Wayne Cawthorne1,2,3,4,5,6
  • Annette V. Jacobsen1,2,3,4,5,6
  • Asha Jois20,1,2,21,3,4,5,6
  • Ashley L. Weir1,2,3,4,5,6
  • Lachlan W. Whitehead1,2,3,4,5,6
  • Pradeep Rajasekhar1,2,22,23,24,25
  • Christopher R. Horne26,1,2,9,4,11
  • Ruqian Lyu1,2,9,10,4,11
  • Lucy J. Mather1,9,10,4,11
  • Raymond K. H. Yip1,9,10,4,11
  • Ellen Tsui1,9,10,4,11
  • Imadh Abdul Azeez1,2,9,10,4,11
  • Tao Tan1,2,9,10,4,11
  • Weiwei Liang27,28,9,10,4,11
  • Suresh Sivanesan7,8,9,10,4,11
  • Andrew Metz7,8,29
  • Ashwin Patwardhan7,8,30,29
  • Natalie Shea7,8,22,23,24,25
  • Guru Iyngkaran7,8,3,4,5,6
  • Daniel Schneider7,8,4,5
  • Alexander Thomas Elford7,8,12,13
  • William Beattie7,8,3,4,5,6
  • Finlay Macrae7,8,3,4,5,6
  • Gianmaria Liccardi31,32,33,3,4,5,6
  • Henning Walczak34,33,4,5,6
  • Yuxia Zhang27,28,35,36,37,4,5
  • Oliver M. Sieber1,2,9,10,3,4,11,5,6
  • Tim D. Spelman1,3,4,5,6
  • Lisa G. Giulino-Roth14,3,4,5,6
  • Michael Christie8,1,21,3,4,5,6
  • Yunshun Chen1
  • Kelly L. Rogers1,2
  • Rory J. Bowden1,2
  • Sandra E. Nicholson1,2
  • Kate E. Lawlor38,39,1
  • Edwin D. Hawkins1,2
  • Britt Christensen7,8,1,2
  • André L. Samson1,2
  • James Edward Vince1,2
  • James M. Murphy26,1,2
39 affiliations
  1. 1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. 2University of Melbourne, Parkville, VIC, Australia
  3. 3Parkville, VIC 305, Australia
  4. 4Parkville, VIC 3052, Australia
  5. 5The Walter and Eliza Hall Institute of Medical Research
  6. 6University of Melbourne
  7. 7Department of Medicine, University of Melbourne, Parkville, VIC, Australia
  8. 8Royal Melbourne Hospital, Parkville, VIC, Australia
  9. 9Department of Medicine, University of Melbourne
  10. 10Parkville, VIC 052, Australia
  11. 11Royal Melbourne Hospital
  12. 12New York, NY 1006, USA
  13. 13Pediatric Hematology/Oncology, Weill Cornell Medical College
  14. 14Pediatric Hematology/Oncology, Weill Cornell Medical College, New York, NY, USA
  15. 15College of Life Sciences, Nankai University
  16. 16Tianjin, 300071, China
  17. 17College of Life Sciences, Nankai University, Tianjin, China
  18. 18Department of Biological Science, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea
  19. 19Royal Children's Hospital
  20. 20Royal Children’s Hospital, Parkville, VIC, Australia
  21. 21Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
  22. 22Clinical Research Center for Pediatric Infection and Immunity, and Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University
  23. 23Guangzhou, 510623, China
  24. 24The Third Affiliated Hospital of Zhengzhou University
  25. 25Zhengzhou, 450052, China
  26. 26Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  27. 27Clinical Research Center for Pediatric Infection and Immunity, and Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University; Guangzhou, China
  28. 28The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  29. 29Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931, Cologne, Germany
  30. 30Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London WC1E 6BT, London, United Kingdom
  31. 31Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  32. 32Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
  33. 33Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany
  34. 34Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
  35. 35Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
  36. 36Clayton, VIC 3168, Australia
  37. 37Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia
  38. 38Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  39. 39Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
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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 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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Cite

BibTeXRIS
BibTeX
@article{pang2026necroptotictoapoptotic,
  title = {{A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease}},
  author = {Jiyi Pang and Aysha Al‐Ani and Komal M. Patel and Yunzhuo Zhou and Samuel N. Young and Jinjin Chen and Isabella Y. Kong and Marilou H. Barrios and James A. Rickard and Siqi Chen and Xiuquan Ma and Farzaneh‐Sadat Rezazadeh‐Shojaee and Seong-Beom Kim and Siavash Foroughi and Wayne Cawthorne and Annette V. Jacobsen and Asha Jois and Ashley L. Weir and Lachlan W. Whitehead and Pradeep Rajasekhar and Christopher R. Horne and Ruqian Lyu and Lucy J. Mather and Raymond K. H. Yip and Ellen Tsui and Imadh Abdul Azeez and Tao Tan and Weiwei Liang and Suresh Sivanesan and Andrew Metz and Ashwin Patwardhan and Natalie Shea and Guru Iyngkaran and Daniel Schneider and Alexander Thomas Elford and William Beattie and Finlay Macrae and Gianmaria Liccardi and Henning Walczak and Yuxia Zhang and Oliver M. Sieber and Tim D. Spelman and Lisa G. Giulino-Roth and Michael Christie and Yunshun Chen and Kelly L. Rogers and Rory J. Bowden and Sandra E. Nicholson and Kate E. Lawlor and Edwin D. Hawkins and Britt Christensen and André L. Samson and James Edward Vince and James M. Murphy},
  journal = {Science},
  year = {2026},
  month = aug,
  doi = {10.1126/science.aeh7112},
  url = {https://doi.org/10.1126/science.aeh7112},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease
AU  - Jiyi Pang
AU  - Aysha Al‐Ani
AU  - Komal M. Patel
AU  - Yunzhuo Zhou
AU  - Samuel N. Young
AU  - Jinjin Chen
AU  - Isabella Y. Kong
AU  - Marilou H. Barrios
AU  - James A. Rickard
AU  - Siqi Chen
AU  - Xiuquan Ma
AU  - Farzaneh‐Sadat Rezazadeh‐Shojaee
AU  - Seong-Beom Kim
AU  - Siavash Foroughi
AU  - Wayne Cawthorne
AU  - Annette V. Jacobsen
AU  - Asha Jois
AU  - Ashley L. Weir
AU  - Lachlan W. Whitehead
AU  - Pradeep Rajasekhar
AU  - Christopher R. Horne
AU  - Ruqian Lyu
AU  - Lucy J. Mather
AU  - Raymond K. H. Yip
AU  - Ellen Tsui
AU  - Imadh Abdul Azeez
AU  - Tao Tan
AU  - Weiwei Liang
AU  - Suresh Sivanesan
AU  - Andrew Metz
AU  - Ashwin Patwardhan
AU  - Natalie Shea
AU  - Guru Iyngkaran
AU  - Daniel Schneider
AU  - Alexander Thomas Elford
AU  - William Beattie
AU  - Finlay Macrae
AU  - Gianmaria Liccardi
AU  - Henning Walczak
AU  - Yuxia Zhang
AU  - Oliver M. Sieber
AU  - Tim D. Spelman
AU  - Lisa G. Giulino-Roth
AU  - Michael Christie
AU  - Yunshun Chen
AU  - Kelly L. Rogers
AU  - Rory J. Bowden
AU  - Sandra E. Nicholson
AU  - Kate E. Lawlor
AU  - Edwin D. Hawkins
AU  - Britt Christensen
AU  - André L. Samson
AU  - James Edward Vince
AU  - James M. Murphy
PY  - 2026
DA  - 2026/08/27
JO  - Science
DO  - 10.1126/science.aeh7112
UR  - https://doi.org/10.1126/science.aeh7112
AB  - 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.
SN  - 0036-8075
SN  - 0193-4511
SN  - 1095-9203
ER  -