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

Chemotherapy-induced intestinal mucositis (CIM) is a severe side effect resulting from disrupted intestinal stem cell homeostasis, yet its molecular drivers remain poorly defined. Multi-omics analysis identified ECSIT as a key regulator of CIM. In vitro and clinical data showed that ECSIT expression is downregulated by chemotherapeutics and correlates negatively with disease severity. Using intestinal epithelium-specific knockout mice, we demonstrated that ECSIT deficiency exacerbates CIM and blocks β-catenin nuclear translocation. Mechanistically, ECSIT stabilizes the β-catenin complex to activate Wnt/β-catenin signaling, thereby maintaining Lgr5+ stem cells, promoting epithelial renewal, and modulating immune balance. Rescue experiments confirmed that restoring ECSIT reverses Wnt signaling inhibition and ameliorates CIM pathology. Our findings establish ECSIT as a critical regulator of mucosal repair via the Wnt pathway and reveal a potential therapeutic target for CIM.