Inflammation-driven Epithelial Remodeling and Persistent Cell-death Signaling Provide New Clues to Inflammatory Bowel Disease Relapse——a Commentary on Pang et al.’s Paper in Science (2026)
- VernacularTitle:炎症驱动的上皮重塑及持续性细胞死亡信号为炎症性肠病复发提供新线索——对Pang等《科学》（2026）论文的评述
- Author:
Xuan DONG
1
;
Jia-Qi ZHANG
1
;
Lian-Xiang LUO
1
Author Information
- Publication Type:Journal Article
- Keywords: inflammatory bowel disease (IBD); epithelial cell death; necroptosis; mitochondrial apoptosis; epithelial remodeling
- From: Progress in Biochemistry and Biophysics 2026;53(10):2733-2738
- CountryChina
- Language:English
- Abstract: Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent mucosal inflammation. Although biologics and small-molecule therapies can effectively suppress inflammation, only 13%-34% of patients achieve deep histological remission, and most experience relapse within 2-3 years. Existing biomarkers, including C-reactive protein (CRP), fecal calprotectin, and endoscopic measures, have limited ability to detect subclinical molecular abnormalities, suggesting that disease-driving factors may persist even during clinical remission. Recently, Pang et al. reported a study in Science that investigated the role of epithelial cell-death signaling using a prospective adult IBD cohort comprising 80 participants and more than 900 biopsy specimens. By integrating bulk and spatial transcriptomics, patient-derived organoids, and 24-36 months of longitudinal follow-up, the authors characterized epithelial cell-death programs associated with IBD persistence. They found that the necroptosis-associated marker pRIPK3 could be detected in the absence of overt histological inflammation and persisted during advanced therapy. IFN‑γ and TNF reshaped the transcriptional landscape of specific colonic epithelial cells, inducing an inflammatory macrophage-like program termed cluster B and triggering RIPK1-independent RIPK3 signaling. This was followed by NOS2/iNOS-mediated mitochondrial apoptosis driving colonocyte death, whereas PUMA-dependent apoptosis contributed to intestinal stem-cell loss. Higher baseline pRIPK3 levels were associated with subsequent disease activity, although their independent predictive value remains to be established. These findings suggest that persistent IBD may reflect not only residual immune inflammation but also inflammation-induced pathological epithelial states. Future therapeutic strategies may therefore need to extend beyond inflammation control toward “molecular repair”, including targeting noncanonical RIPK3 signaling, modulating iNOS/PUMA-dependent mitochondrial apoptosis, and developing relapse-risk stratification strategies based on tissue biomarkers such as pRIPK3. Such approaches may help shift the therapeutic goal from “clinical remission” toward “molecular healing”.
