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

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract characterized by a 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. Conventional approaches aimed at suppressing neutrophil activity have achieved only modest clinical efficacy and highlight the need for strategies that recalibrate neutrophil responses without compromising their essential antimicrobial functions. In this study, we employed high-throughput chemical screening using neutrophil-specific transgenic zebrafish larvae to identify compounds capable of modulating neutrophil homeostasis, and subsequently evaluating their efficacy in a dextran sodium sulfate (DSS)-induced IBD model. We identified epothilone B (Epo B), a traditional chemotherapeutic drug, as a potential therapeutic candidate for IBD. Our findings demonstrate that Epo B protects against IBD by promoting intestinal epithelial recovery, alleviating inflammatory responses, and rebalancing the gut microbiota. Mechanistically, Epo B selectively stimulates neutrophil apoptosis by targeting and enhancing Caspase-3 cleavage, thereby inhibiting neutrophilic inflammation. This study underscores the utility of in vivo high-throughput drug screening in IBD and highlights Epo B as a promising candidate for drug repurposing in IBD treatment, offering a novel therapeutic strategy by targeting neutrophil apoptosis.