Introduction Eosinophilic oesophagitis (EoE) is a chronic Th2-mediated inflammatory disease characterized by epithelial barrier dysfunction, basal cell hyperplasia and persistent mucosal remodeling. Even after inflammatory control, epithelial transcriptomic and histologic abnormalities often persist, contributing to ongoing symptoms and disease relapse.
Introduction
Eosinophilic oesophagitis (EoE) is a chronic Th2-mediated inflammatory disease characterized by epithelial barrier dysfunction, basal cell hyperplasia and persistent mucosal remodeling. Even after inflammatory control, epithelial transcriptomic and histologic abnormalities often persist, contributing to ongoing symptoms and disease relapse. Identifying molecular regulators of epithelial dysfunction remains a major therapeutic priority.
Problem Statement
Current EoE therapies primarily target inflammation but incompletely restore epithelial homeostasis. The mechanisms linking IL-13-driven inflammation to impaired epithelial differentiation and excessive proliferation are incompletely understood, limiting development of therapies that promote durable mucosal healing.
Summary
This translational study identifies forkhead box M1 (FOXM1) as a central transcriptional regulator of epithelial remodeling in EoE. FOXM1 expression was markedly increased in active EoE and localized predominantly to the basal epithelial layer. IL-13 stimulation upregulated FOXM1 in oesophageal epithelial cells, organoids and murine EoE models, linking Th2 inflammation directly to epithelial proliferative signaling. Functional inhibition of FOXM1 using the small-molecule inhibitor RCM-1 or siRNA restored epithelial differentiation markers including involucrin and filaggrin, reduced basal cell hyperplasia, suppressed proliferation and improved epithelial barrier integrity. In murine EoE models, FOXM1 inhibition reduced eosinophilic inflammation and reversed histologic remodeling. Mechanistically, FOXM1 directly regulated the cell-cycle gene cyclin B1 (CCNB1), driving epithelial proliferation through altered G2/M transition. The study further demonstrated that IL-13 activates a non-canonical PI3K/AKT–FOXM1 signaling axis, while FOXM1 inhibition reduced STAT6 phosphorylation and suppressed eotaxin-3 (CCL26) expression, indicating simultaneous modulation of epithelial and inflammatory pathways. Importantly, FOXM1 overexpression independently induced epithelial hyperplasia and proliferation even without IL-13 stimulation, reinforcing its pathogenic role. These findings position FOXM1 as a novel therapeutic target capable of simultaneously restoring epithelial differentiation, improving barrier function and attenuating allergic inflammation in EoE. The work also highlights a paradigm shift toward epithelial-directed therapeutic strategies in EoE beyond eosinophil suppression alone.
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