Pathogenesis of Eosinophilic Esophagitis: A PRISMA-based systematic review of Genetic, Immunological and Molecular Drivers

BACKGROUND/OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic, antigen-driven inflammatory disease characterized by esophageal dysfunction and tissue remodeling. Despite increasing prevalence, its pathogenesis remains incompletely understood. This review aims to systematically synthesize current evidence on the immunological, genetic, epithelial, and extracellular matrix mechanisms driving EoE. The goal is to identify upstream molecular targets and biomarkers to support precision medicine approaches. METHODS: A PRISMA-based systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2014 and June 2025. Eligibility criteria were defined using the PECOS model, focusing on studies reporting quantitative biomolecular data. Risk of bias was assessed using validated tools for observational, in vivo, and in vitro studies. A total of 103 original research articles were included and categorized into four mechanistic domains. RESULTS: The review identified epithelial barrier dysfunction, type 2 inflammation, and fibroblast activation as central features of EoE. Key cytokines (IL-4, IL-5, IL-13, TSLP) and transcriptional regulators (e.g., GATA-3, KLF5, RELM-α) were implicated in disease progression. Genetic and epigenetic analyses revealed susceptibility loci and persistent molecular alterations. Novel therapeutic targets and biomarkers were proposed, including TSLPR+ Th2A cells, LIGHT-HVEM axis, and CD73 metabolic checkpoints. CONCLUSIONS: EoE is a multifactorial disease involving complex immune-epithelial-stromal interactions. This review highlights emerging molecular pathways and supports a shift toward biomarker-guided, stratified treatment strategies. Integration of multi-omics data and age-stratified analyses enhances understanding of disease heterogeneity. Future research should focus on longitudinal studies, pediatric cohorts, and validation of non-invasive biomarkers.