CLDN15 encodes claudin-15, a tight junction protein that forms paracellular channels permeable to cations and water in epithelial tissues. The protein functions by polymerizing in tight junction strands to create selective channels that regulate paracellular permeability 1. Mechanistically, CLDN15 contains a critical aspartic acid residue at position 55 (D55) that plays a dual role in determining both electrostatic and steric properties of the pore, with its electrostatic function being more prominent in cation selectivity 1. In the gastrointestinal tract, CLDN15 facilitates sodium and water transport, indirectly impacting nutrient absorption 1. Disease relevance includes its role in intestinal barrier dysfunction, where HIF2α-induced CLDN15 transcription contributes to compromised barrier integrity and arthritis exacerbation 2. Additionally, CLDN15 serves as a diagnostic marker for malignant pleural mesothelioma, showing 83% positivity in tumor samples with 92% specificity 3. Clinically, CLDN15 expression is paradoxically increased in environmental enteric dysfunction despite malabsorption symptoms 4, and its expression enhances during intestinal organoid maturation in transplantation models 5. DNA methylation alterations at CLDN15 are associated with in-utero diabetes exposure 6, suggesting potential early-life biomarker utility.