Sasaki Masaru, Wang Joshua X, Zhou Yusen, Kennedy Kanak V, Teranishi Ryugo, Itami Takefumi, Ishikawa Satoshi, Hara Takeo, Winters Heidi, McMillan Emily A, Mahon Mark, Golden Hailey, Dhakal Diya, Bacarella Alyssa, Umeweni Chizoba N, Wilkins Benjamin J, Karakasheva Tatiana A, Whelan Kelly A, Shaffer Sydney M, Ruffner Melanie A, Muir Amanda B
bioRxiv. 2025 May 28:2025.05.25.655133. doi: 10.1101/2025.05.25.655133.
Eosinophilic esophagitis (EoE) is a chronic allergic disease characterized by esophageal epithelial remodeling, barrier dysfunction, and inflammation. Despite histologic remission, molecular and structural changes in the epithelium persist, contributing to ongoing symptoms and relapse. The transcription factor FOXM1 has been shown to be a key regulator of epithelial proliferation and inflammation in allergic asthma.
To investigate the role of FOXM1 in epithelial disruption in EoE and to evaluate the therapeutic potential of FOXM1 inhibition.
FOXM1 expression was analyzed in human esophageal biopsies, patient-derived organoids, and murine EoE models. IL-13 stimulation was used to model EoE in vitro. The effects of FOXM1 inhibition via the small molecule RCM-1 and siRNA-mediated knockdown were assessed by histology, gene expression profiling, organoid formation rates, and barrier integrity assays. RNA sequencing and chromatin immunoprecipitation were performed to elucidate molecular mechanisms.
FOXM1 was significantly upregulated in patients with active EoE and localized to the basal epithelium. IL-13 increased FOXM1 expression, which impaired epithelial differentiation and enhanced basal cell hyperplasia. FOXM1 inhibition restored differentiation markers, reduced basal hyperplasia, and improved barrier function. In murine models, RCM-1 ameliorated epithelial changes and decreased eosinophil infiltration. Mechanistically, FOXM1 directly regulated cell cycle gene, CCNB1, which was upregulated in EoE and downregulated upon FOXM1 inhibition. FOXM1 expression was driven by an IL-13-PI3K/AKT axis.
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.
Eosinophilic esophagitis is marked by epithelial remodeling and barrier dysfunction driven by Th2 inflammation. Despite remission, molecular and histologic changes in the esophageal epithelium persist, contributing to symptoms and relapse. The mechanisms underlying this epithelial dysregulation remain poorly understood. This study identifies FOXM1 as a key transcriptional regulator of epithelial disruption in EoE, demonstrating that FOXM1 inhibition restores epithelial differentiation, reduces basal cell hyperplasia, improves barrier integrity, and mitigates inflammation. Targeting FOXM1 offers a novel therapeutic strategy to restore epithelial homeostasis and reduce inflammation in EoE. This dual approach, addressing both epithelial and immune dysregulation, may guide future therapeutic development and improve patient outcomes.
嗜酸性粒细胞性食管炎（EoE）是一种慢性过敏性疾病，其特征为食管上皮重塑、屏障功能障碍和炎症。尽管组织学上已缓解，但上皮中的分子和结构变化仍然存在，导致症状持续和复发。转录因子FOXM1已被证明是过敏性哮喘中上皮增殖和炎症的关键调节因子。
研究FOXM1在EoE上皮破坏中的作用，并评估抑制FOXM1的治疗潜力。
在人食管活检组织、患者来源的类器官和小鼠EoE模型中分析FOXM1表达。使用白细胞介素-13（IL-13）刺激在体外模拟EoE。通过组织学、基因表达谱分析、类器官形成率和屏障完整性测定评估小分子RCM-1和小干扰RNA（siRNA）介导的敲低对FOXM1的抑制作用。进行RNA测序和染色质免疫沉淀以阐明分子机制。
在活动性EoE患者中，FOXM1显著上调，并定位于基底上皮。IL-13增加了FOXM1的表达，这损害了上皮分化并增强了基底细胞增生。抑制FOXM1可恢复分化标志物，减少基底增生，并改善屏障功能。在小鼠模型中，RCM-1改善了上皮变化并减少了嗜酸性粒细胞浸润。从机制上讲，FOXM1直接调节细胞周期基因CCNB1，该基因在EoE中上调，在抑制FOXM1后下调。FOXM1的表达由IL-13-磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/AKT）轴驱动。
FOXM1通过驱动增殖和损害分化在EoE上皮破坏中起关键作用。靶向FOXM1可恢复上皮稳态，减轻炎症，并为EoE提供一种新的治疗方法。
嗜酸性粒细胞性食管炎的特征是由辅助性T细胞2（Th2）炎症驱动的上皮重塑和屏障功能障碍。尽管病情缓解，但食管上皮的分子和组织学变化仍然存在，导致症状和复发。这种上皮失调的潜在机制仍知之甚少。本研究确定FOXM1是EoE上皮破坏的关键转录调节因子，表明抑制FOXM1可恢复上皮分化，减少基底细胞增生，改善屏障完整性，并减轻炎症。靶向FOXM1提供了一种新的治疗策略，以恢复上皮稳态并减轻EoE中的炎症。这种针对上皮和免疫失调的双重方法可能会指导未来的治疗发展并改善患者预后。
