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

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.