CLDN3 (claudin 3) is a barrier-forming tight junction protein that plays a critical role in maintaining epithelial cell-cell adhesion and intercellular space obliteration through calcium-independent mechanisms 1. Beyond its structural function, CLDN3 expression is frequently dysregulated in multiple disease contexts. In cholangiocarcinoma, TET1-mediated CLDN3 promoter demethylation promotes epithelial-mesenchymal transition (EMT), while PPM1G-catalyzed TET1 dephosphorylation suppresses this pathway, suggesting therapeutic potential 2. In hepatocellular carcinoma, aberrant CLDN3 expression drives cancer progression through loss of intercellular adhesion and altered cell signaling 3. In colorectal cancer, HSF1 directly activates CLDN3 transcription to enhance cell proliferation, invasion, and migration 4. Conversely, reduced CLDN3 expression associates with pregnancy-induced hypertension, where upregulation promotes trophoblast proliferation and invasion via MMP/ERK1/2 pathways 5. CLDN3 promoter hypermethylation is common in esophageal squamous cell carcinoma and precursor lesions, enabling early detection 6. Recently, CLDN3 emerged as a glycolysis-related biomarker in gastric cancer 7 and immune-metabolic dysregulation in acute pancreatitis 8. Clinically, CLDN3's minimal expression in normal tissues coupled with tumor co-expression with EpCAM makes it an attractive target for bispecific antibody-drug conjugates 1.