ADD3 (adducin 3) is a membrane-cytoskeleton-associated protein that promotes spectrin-actin network assembly and actin filament capping 1. Its primary functions include regulating actin cytoskeleton organization, cell morphology, and barrier function across multiple tissues. Mechanistically, ADD3 stabilizes the actin cytoskeleton through G-actin and F-actin ratio regulation and coordinates expression of focal adhesion proteins and tight junction proteins 2. In cholangiocytes, ADD3 recruits βII-spectrin to cell membranes and maintains tight junction integrity; loss-of-function mutations impair barrier function and increase paracellular permeability 2. In glioblastoma stem cells, ADD3 regulates cell morphology and tumor-tumor connections through actin cytoskeleton stability 3. Disease relevance is substantial. ADD3 genetic variants (particularly rs17095355 and rs2501577) are strongly associated with biliary atresia (BA) susceptibility across Asian and Caucasian populations 4567. ADD3 loss-of-function causes defective cholangiocyte differentiation and increased BA severity in experimental models 2. Additionally, ADD3 alternative splicing dysregulation promotes lung cancer progression 8, and ADD3 knockout impairs renal blood flow autoregulation and enhances hypertensive renal injury 9. Clinically, ADD3 variants represent tractable biomarkers for BA risk stratification and potential therapeutic targets for genetic liver diseases, lung cancer, and hypertensive nephropathy.