CLDN5 encodes claudin-5, a critical tight junction protein that maintains blood-brain barrier (BBB) integrity by limiting passive diffusion of ions and solutes across brain microvascular endothelial cells 1. The protein's expression is tightly regulated by other junctional proteins, pericytes, and astrocytes 1. CLDN5 functions through multiple mechanisms including regulation by epigenetic factors like HDAC1 and EZH2, which control its transcriptional expression 23. Under pathological conditions, CLDN5 can be redistributed from cell membranes to cytoplasm via CAV1-mediated mechanisms, where autophagy helps degrade aggregated protein to protect BBB integrity 4. Disease relevance is significant, as compromised BBB function due to CLDN5 decline increases risks of neuropsychiatric disorders, epilepsy, and dementia 1. Loss of CLDN5 allows peripheral inflammatory cytokines like TNF-α to infiltrate the brain, contributing to depression-like behaviors 23. Microglia play a dual role in BBB maintenance by initially expressing CLDN5 to maintain barrier function, but later phagocytosing astrocytic end-feet during sustained inflammation 5. Beyond CNS disorders, CLDN5 also plays roles in tumor growth, metastasis, and various non-neurological diseases 67.