TJP3 (tight junction protein 3) is a scaffolding protein that links tight junction transmembrane proteins including claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton, functioning to limit paracellular movement of substances and maintain epithelial/endothelial barrier integrity 1. Unlike its homologs TJP1 and TJP2, TJP3 is dispensable for normal development and tight junction establishment in standard laboratory conditions. Beyond barrier function, TJP3 promotes cell-cycle progression through sequestration of cyclin D1 at tight junctions during mitosis 2. TJP3 has emerged as a significant player in disease pathology. In breast cancer, TJP3 upregulation increases chemoresistance to paclitaxel and promotes tumor metastasis and immunotherapy escape, correlating negatively with PD-L1 expression 3. In oral squamous cell carcinoma, TJP3 represents the only common prognostic marker for both radiotherapy and concurrent chemoradiotherapy resistance, with significantly altered expression between radiosensitive and radioresistant cell lines 4. TJP3 also appears in prognostic signatures for head and neck squamous cell carcinoma 5. Additionally, HDAC inhibitors enhance TJP3 expression in retinal pigment epithelium cells under oxidative stress, contributing to cytoskeletal protection 6. In COVID-19 patients, elevated gut commensal Akkermansia muciniphila associates with heightened TJP3 expression 7, while dysregulated TJP3 expression has been identified in Alzheimer's disease and adenomyosis pathogenesis 89.