CLDN4 (claudin 4) is a tetraspan transmembrane tight junction protein that regulates paracellular permeability and barrier function through dynamic interactions with other claudins 12. The protein cannot form tight junction strands independently but associates with other claudins to modulate barrier properties - it may coassemble with CLDN8 to form anion-selective channels for chloride permeability in renal collecting ducts, integrate with CLDN3 strands to regulate localized barrier function, and disrupt channel-forming CLDN2 and CLDN15 to inhibit cation conductance 12. CLDN4 is significantly overexpressed in multiple cancer types including hepatocellular carcinoma, ovarian cancer, pancreatic cancer, and non-small-cell lung cancer, where it promotes drug resistance, metastasis, and poor prognosis 3456. In hepatocellular carcinoma, palmitoylation at cysteine residues C104 and C107 anchors CLDN4 to lipid rafts, facilitating hepatic-to-biliary lineage transition and lenvatinib resistance through Notch signaling activation 3. Additionally, CLDN4 contributes to inflammatory diseases like atopic dermatitis and acute pancreatitis by promoting ferroptosis and inflammation via the JAK2/STAT3 pathway 78. These findings establish CLDN4 as both a critical barrier function regulator and promising therapeutic target.