Work

High-throughput chemical screen identifies epothilone B in modulating inflammatory bowel disease by triggering neutrophil apoptosis

Year: 2025

Type: article

Abstract: Background Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract characterized by complex interplay of genetic, environmental, and immunological factors. Neutrophils, as a key component of the innate immune system, play a critical role in IBD pathogenesis due to their dysregulated infiltration, impaired apoptosis, and resultant epithelial damage during the disease process.However, effective intervention strategies by modulating neutrophils to mitigate the severity of IBD have yet to be established. Methods High-throughput chemical screening was conducted utilizing neutrophil-specific transgenic zebrafish embryos to identify compounds capable of modulating neutrophil homeostasis. The identified compounds were subsequently evaluated in a dextran sodium sulfate (DSS)-induced zebrafish model of IBD by assessing intestinal damage, leukocyte infiltration, the expression of inflammatory cytokines, and alterations in intestinal bacterial microbiota. The effects of Epothilone B (Epo B) on neutrophil apoptosis were assessed via flow cytometry and whole-mount terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays, both in vivo and in vitro. Potential targets of Epo B in the context of IBD were identified through network pharmacology and molecular docking analyses, followed by validation at the protein level via Western blotting. Results Chemical screening identified four compounds, including Epo B, that influence neutrophil homeostasis. Epo B protects against IBD in zebrafish by promoting intestinal epithelial recovery, alleviating inflammatory responses, and rebalancing gut microbiota. Mechanistically, Epo B selectively stimulates neutrophil apoptosis by targeting and enhancing Caspase-3 cleavage, thereby inhibiting neutrophilic inflammation. Conclusion This study underscores the utility of zebrafish in drug screening for IBD and highlights Epo B as a promising candidate for repurposing in IBD treatment, offering a novel therapeutic strategy by targeting neutrophil apoptosis.

Source: Genes & Diseases

DOI: 10.1016/j.gendis.2025.102009