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

• 成果类型: Article
• 署名作者: Pang, Jiyi; Al-Ani, Aysha H.; Patel, Komal M.; Zhou, Yunzhuo; Young, Samuel N.; Chen, Jinjin; Kong, Isabella; Barrios, Marilou; Rickard, James A.; Chen, Siqi; Ma, Xiuquan; Shojaee, Farzaneh; Kim, Seong-Beom; Foroughi, Siavash; Cawthorne, Wayne; Jacobsen, Annette V.; Jois, Asha; Weir, Ashley L.; Whitehead, Lachlan W.; Rajasekhar, Pradeep; Horne, Christopher R.; Lyu, Ruqian; Mather, Lucy J.; Yip, Raymond K. H.; Tsui, Ellen; Azeez, Imadh; Tan, Tao; Liang, Weiwei; Sivanesan, Suresh; Metz, Andrew; Patwardhan, Ash; Shea, Natalie; Iyngkaran, Guru; Schneider, Daniel; Elford, Alexander T.; Beattie, William; Macrae, Finlay; Liccardi, Gianmaria; Walczak, Henning; Zhang, Yuxia; Sieber, Oliver M.; Spelman, Tim; Giulino-Roth, Lisa; Christie, Michael; Chen, Yunshun; Rogers, Kelly L.; Bowden, Rory; Nicholson, Sandra E.; Lawlor, Kate E.; Hawkins, Edwin D.; Christensen, Britt; Samson, Andre L.; Vince, James E.; Murphy, James M.
• 署名单位: Walter & Eliza Hall Institute; University of Melbourne; Melbourne Health; Royal Melbourne Hospital; University of Melbourne; Cornell University; Weill Cornell Medicine; Nankai University; Ulsan National Institute of Science & Technology (UNIST); Royal Children's Hospital Melbourne; Monash University; Guangzhou Medical University; Zhengzhou University; University of Cologne; University of Cologne; University of Cologne; University of London; University College London; Hudson Institute of Medical Research; Monash University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeh7112
• 发表日期: 2026-08-27
• 页码: eaeh7112
• 关键词: RECEPTOR-INTERACTING PROTEIN; cell-death; ulcerative-colitis; crohns-disease; programmed necrosis; caspase-8; tnf; activation; rip3; mlkl

摘要

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.