CAPN14 encodes a calcium-dependent cysteine protease with unique expression patterns in the upper gastrointestinal tract, particularly in esophageal squamous epithelium 1. The protein functions as a calcium-regulated non-lysosomal thiol-protease involved in epithelial barrier regulation and tissue remodeling. CAPN14 expression is dynamically regulated by IL-13 through STAT6-mediated transcriptional activation, with STAT6 binding sites in the promoter and first intron being essential for IL-13-induced upregulation 2. The protease impairs esophageal epithelial barrier function by promoting loss of desmoglein-1 expression and has regulatory roles in repairing IL-13-induced epithelial changes 1. CAPN14 is strongly associated with eosinophilic esophagitis (EoE), a chr2 allergic inflammatory disorder, where genetic variants at the 2p23 locus containing CAPN14 represent unique EoE susceptibility elements 34. The gene is positioned in an epigenetic hotspot and is part of the core EoE proinflammatory transcriptome alongside CCL26, ALOX15, ANO1, and TNFAIP6 5. CAPN14 represents a potential therapeutic target for EoE and related eosinophilic diseases due to its tissue-specific expression and central role in epithelial dysfunction 16.