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