FOXM1 inhibition reduces IL-13-induced epithelial remodelling and inflammation in eosinophilic oesophagitis.

Abstract

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic allergic disease characterised by oesophageal epithelial remodelling, barrier dysfunction and inflammation. The transcription factor forkhead box M1 (FOXM1) has been shown to be a key regulator of epithelial proliferation and inflammation in allergic asthma. OBJECTIVE: To investigate the role of FOXM1 in epithelial disruption in EoE and to evaluate the therapeutic potential of FOXM1 inhibition. DESIGN: FOXM1 expression was analysed in human oesophageal biopsies, patient-derived organoids and murine EoE models. Interleukin (IL)-13 stimulation was used to model EoE in vitro. Using FOXM1 inhibition via the small molecule Robert Costa Memorial drug-1 (RCM-1), small interfering RNA-mediated knockdown or FOXM1 overexpression, the roles of FOXM1 were assessed by histology, gene expression profiling, organoid formation rates, barrier integrity and proliferation assays. RNA sequencing and chromatin immunoprecipitation were performed to elucidate molecular mechanisms. RESULTS: FOXM1 was significantly upregulated in patients with active EoE and localised to the basal epithelium. IL-13 increased FOXM1 expression in vitro. FOXM1 inhibition restored differentiation markers, reduced basal cell hyperplasia and proliferation, and improved barrier function. In a murine model, RCM-1 reduced epithelial changes and eosinophil infiltration. Conversely, FOXM1 overexpression promoted basal cell hyperplasia and proliferation. Mechanistically, FOXM1 directly regulated cell cycle gene, cyclin B1, which was upregulated in EoE and downregulated on FOXM1 inhibition. RCM-1 reduced phosphorylated STAT6 under IL-13 stimulation. FOXM1 expression was driven in part by an IL-13-PI3K/AKT axis. CONCLUSION: FOXM1 plays a pivotal role in epithelial disruption in EoE by driving proliferation and impairing differentiation. Targeting FOXM1 restores epithelial homeostasis, mitigates inflammation and offers a novel therapeutic approach for EoE.