ESYT3 (Extended Synaptotagmin 3) is a multi-C2 domain endoplasmic reticulum membrane protein that functions as a lipid transporter at ER-plasma membrane contact sites 1. The protein creates junctions between the ER and plasma membrane to facilitate calcium-dependent exchange of glycerophospholipids between apposed membranes 1. ESYT3 can hetero- and homodimerize with other Extended Synaptotagmins and binds phospholipids through its C2 domains 2. In epithelial cells, ESYT3 regulates ion transport by controlling phosphatidylserine levels at ER/PM nanodomains, with its lipid transfer activity and C2C domain being essential for function 3. During adipocyte differentiation, ESYT3 undergoes proteolytic cleavage and targets lipid droplets from a specialized ER structure called the primordial cisterna 4. Despite its cellular importance, ESYT3 knockout mice develop normally and remain viable, though cultured cells show reduced migration and stress resistance 1. Clinically, ESYT3 variants have been associated with coronary artery disease in Han Chinese females 5, lung adenocarcinoma prognosis 6, and foveal hypoplasia features 78. In mice, ESYT3 depletion improved chloride flux and fluid secretion in salivary glands and pancreatic ducts 3.