CLDN3 encodes claudin-3, a barrier-forming tight junction protein that mediates calcium-independent cell adhesion and maintains the structural integrity of epithelial barriers by obliterating intercellular spaces. Beyond its canonical role in tight junction assembly and transepithelial transport regulation, CLDN3 has emerged as a significant driver in multiple malignancies. In colorectal cancer, heat shock transcription factor 1 directly activates CLDN3 transcription to promote cell proliferation, invasion, and migration 1. Similarly, in cholangiocarcinoma, aberrant CLDN3 upregulation—driven by TET1-mediated promoter demethylation—facilitates epithelial-mesenchymal transition and poor prognosis 2. CLDN3 is highly co-expressed with EpCAM across multiple solid tumors but shows minimal expression in normal tissues, positioning it as an attractive therapeutic target. Bispecific antibody-drug conjugates targeting both EpCAM and CLDN3 demonstrate potent tumor cell growth inhibition with reduced toxicity to normal tissues 3. In ovarian cancer, CLDN3 overexpression correlates with poorer survival outcomes and has emerged as both a diagnostic biomarker and therapeutic target, including sensitivity to Clostridium perfringens enterotoxin 4. Gene methylation of CLDN3 occurs frequently in esophageal squamous cell carcinoma and its precursor lesions, with potential utility in early screening 5. These findings establish CLDN3 as a multifunctional protein whose dysregulation drives cancer progression across diverse epithelial malignancies.