{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Masaru Sasaki"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Joshua X Wang"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Ryugo Teranishi"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Takefumi Itami"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Yusen Zhou"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Pediatrics, Stanford University School of Medicine, Stanford, California, USA"
      ],
      "name": "Kanak V Kennedy"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Ann Semeao"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Satoshi Ishikawa"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Takeo Hara"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Emily A McMillan"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Mark Mahon"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Hailey Golden"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Diya Dhakal"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Alyssa Baccarella"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Heidi Winters"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Chizoba N Umeweni"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Benjamin J Wilkins"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Tatiana A Karakasheva"
    },
    {
      "affiliations": [
        "Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA",
        "Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Kelly A Whelan"
    },
    {
      "affiliations": [
        "Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Sydney M Shaffer"
    },
    {
      "affiliations": [
        "Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Melanie A Ruffner"
    },
    {
      "affiliations": [
        "Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Amanda B Muir"
    }
  ],
  "title": "FOXM1 inhibition reduces IL-13-induced epithelial remodelling and inflammation in eosinophilic oesophagitis",
  "uid": "9c6f1a96-e68b-51ef-8a11-6a35a6b4c111"
}