This study reveals the central regulatory role of FOXM1 in epithelial barrier dysfunction in eosinophilic esophagitis (EoE), providing new experimental design insights for EoE mechanism research and targeted interventions, suggesting that targeting epithelial proliferation-differentiation imbalance may enhance treatment durability.
Literature Overview
The article titled 'FOXM1 inhibition reduces IL-13-induced epithelial remodelling and inflammation in eosinophilic oesophagitis,' published in the journal Gut, systematically investigates the role of the transcription factor FOXM1 in epithelial remodeling in eosinophilic esophagitis (EoE) and its potential as a therapeutic target. By integrating patient samples, organoid models, and mouse models, the research team reveals the pivotal role of FOXM1 in IL-13-driven epithelial proliferation and differentiation imbalance, offering new strategies for restoring epithelial homeostasis.Background Knowledge
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease characterized by esophageal epithelial barrier dysfunction, basal cell hyperplasia, and persistent inflammation. Even during periods of inflammatory remission, molecular alterations in the epithelium persist, leading to symptom recurrence and disease progression. Current treatments primarily focus on suppressing immune responses (e.g., corticosteroids) or eliminating allergens, but durable mucosal healing remains difficult to achieve. The mechanisms underlying epithelial cell-autonomous dysfunction are not fully understood, particularly the molecular switches driving excessive basal cell proliferation and impaired terminal differentiation. The transcription factor FOXM1 has been reported to regulate epithelial proliferation in allergic diseases such as asthma, but its role in EoE remains unclear. This study addresses this knowledge gap by proposing that FOXM1 may serve as a key node linking Th2 inflammation to epithelial remodeling, thereby providing an entry point for developing novel therapies targeting epithelial homeostasis.
Research Methods and Experiments
The research team employed a multi-level experimental system to validate the function of FOXM1: first, using public RNA-seq datasets (GSE58640) and patient esophageal biopsy samples, they confirmed that FOXM1 is significantly upregulated in patients with active EoE and localized to the basal epithelial layer. Subsequently, using the EPC2-hTERT cell line and patient-derived organoid (PDO) models to simulate the IL-13-induced EoE microenvironment, they found that IL-13 induces FOXM1 expression via the PI3K/AKT signaling pathway. Using the small-molecule inhibitor RCM-1 or siRNA-mediated knockdown of FOXM1, they significantly restored expression of terminal differentiation markers (e.g., IVL, FLG), suppressed basal cell hyperplasia and proliferation (Ki-67), and improved barrier function in air-liquid interface (ALI) culture models (increased TEER values). In a mouse model of EoE, RCM-1 treatment not only reduced epithelial remodeling but also decreased esophageal eosinophil infiltration, suggesting dual anti-inflammatory and epithelial repair effects.Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a new direction for EoE treatment strategies—shifting from purely anti-inflammatory approaches to restoring epithelial homeostasis. Targeting FOXM1 may enable more durable mucosal healing and reduce relapse. Moreover, as a node of epithelial-immune crosstalk, FOXM1 inhibitors could become dual-function drugs with both anti-inflammatory and barrier-repair capabilities, improving treatment response rates.
From a drug development perspective, RCM-1, as a small-molecule degrader, demonstrates strong efficacy in vitro and in vivo, warranting further optimization of pharmacokinetic properties and long-term safety evaluation. Future studies could explore more specific FOXM1 inhibition strategies, such as protein-protein interaction inhibitors, to minimize off-target effects.
In terms of disease modeling, this study highlights the importance of combining patient-derived organoids with ALI systems, providing a reliable platform for high-throughput screening of EoE therapeutics. Additionally, FOXM1 expression levels could serve as a biomarker in clinical trials to assess epithelial repair, facilitating precision medicine.
Conclusion
This study establishes the central pathogenic role of FOXM1 in eosinophilic esophagitis (EoE), revealing it as a downstream effector of IL-13 that drives excessive epithelial proliferation and blocks terminal differentiation by activating CCNB1, leading to barrier dysfunction. Targeting FOXM1 not only reverses epithelial remodeling but also indirectly suppresses CCL26-mediated eosinophil infiltration, achieving dual therapeutic effects. This finding provides a solid foundation for shifting the EoE treatment paradigm from pure immunosuppression toward epithelial homeostasis restoration. From bench to bedside, FOXM1 inhibitors hold promise as next-generation therapeutics, particularly for patients with refractory or frequently recurring disease. Furthermore, FOXM1 expression levels may serve as a biomarker to assess the degree of mucosal healing, guiding personalized treatment. Combined with patient-derived organoid models, this study also advances the development of precise disease modeling and drug screening platforms, offering powerful tools for future translational research. In summary, this study provides key theoretical insights and potential intervention targets for improving long-term outcomes in EoE patients.
