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  3. A protective role of ECSIT in chemotherapy-induced intestinal mucositis by maintaining Lgr5+ intestinal stem cells and gut homeostasis

A protective role of ECSIT in chemotherapy-induced intestinal mucositis by maintaining Lgr5+ intestinal stem cells and gut homeostasis

  • Life Sci. 2026 Mar 15:389:124236. doi: 10.1016/j.lfs.2026.124236.
Shuai Wang 1,  Yuying Jiang 2,  Jie Yu 3,  Pingping Cao 4,  Yan Chen 1,  Tianqi Shen 4,  Jukun Zhang 1,  Shuo Yang 5,  Ping Wang 6,  Fan Lin 7,  Yingjian Zhang 8
Affiliations

Affiliations

  • 1 Henan Medical Key Laboratory of Gastrointestinal Microecology and Hepatology, Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.
  • 2 Department of Immunology, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Gusu School, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, National Vaccine Innovation Platform, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 3 School of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China.
  • 4 Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 5 Department of Immunology, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Gusu School, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, National Vaccine Innovation Platform, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 6 School of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan, China. Electronic address: [email protected].
  • 7 Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
  • 8 Henan Medical Key Laboratory of Gastrointestinal Microecology and Hepatology, Department of Gastroenterology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address: [email protected].
PMID: 41611204 DOI: 10.1016/j.lfs.2026.124236
Abstract

Aims: Chemotherapy-induced intestinal mucositis (CIM) is a common and severe side effect linked to disrupted intestinal stem cell (ISC) balance, though its molecular regulation remains unclear. The principal objective of this research was to elucidate the role of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) in intestinal stem cell balance and mucosal repair during CIM, with a specific focus on the Wnt/β-catenin pathway.

Materials and methods: This study used multi-omics and gene editing to elucidate ECSIT's role in intestinal stem cell balance and mucosal repair via the Wnt/β-catenin pathway. Multi-omics and Gene Set Enrichment Analyses (GSEA) identified ECSIT as a key CIM regulator.

Key findings: Chemotherapeutic drugs dose-dependently reduced ECSIT expression in intestinal epithelial cells. Clinical analysis revealed that ECSIT expression decreased with increasing pathological severity (normal > inflammation > adenocarcinoma). In intestinal epithelium-specific knockout mice, ECSIT deficiency worsened irinotecan (CPT11)-induced CIM and blocked β-catenin nuclear translocation. ECSIT stabilized the β-catenin complex, regulating Wnt target genes like Axis inhibition protein (AXIN) and Cyclin D1 (CCND1); its knockout reduced Wnt signaling. Single-cell Sequencing (scRNA-seq) revealed that ECSIT knockout reduced Lgr5 stem cells and increased inflammatory cell infiltration. Lgr5-specific inducible knockout and ECSIT complementation demonstrated that restoring ECSIT reversed β-catenin inhibition and improved CIM pathology.

Significance: This study clarified ECSIT's dual role in stabilizing β-catenin and sustaining Wnt signaling-regulating Lgr5 intestinal stem cell proliferation and differentiation, epithelial renewal, and immune balance. These findings offer insights into CIM pathogenesis and establish the basis for developing targeted therapy through ECSIT-Wnt axis regulation.

Keywords

Chemotherapy-induced intestinal mucositis; ECSIT; Intestinal stem cells; Lgr5; Wnt/β-catenin pathway.

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