ESYT1 (Extended Synaptotagmin 1) is a calcium-sensing protein that functions as a molecular tether between intracellular membranes and the plasma membrane. Upon calcium elevation, ESYT1 translocates to endoplasmic reticulum (ER)-plasma membrane (ER-PM) contact sites via its C2 calcium-binding domains, facilitating membrane tethering and contact site formation 12. ESYT1 also localizes to mitochondria-ER contact sites (MERCs) where it forms complexes with SYNJ2BP to regulate mitochondrial calcium and lipid homeostasis 3. Mechanistically, ESYT1 mediates non-vesicular lipid transfer through its SMP domain, including fatty acid mobilization from lipid droplets for mitochondrial β-oxidation 4 and HDL-derived cholesterol redistribution to intracellular compartments 5. ESYT1 acts as a signaling suppressor of the ADGRD1 G-protein-coupled receptor in the absence of cytosolic calcium, with calcium-induced dissociation relieving this inhibition 6. Disease relevance includes roles in glioblastoma progression, sarcopenic obesity pathogenesis through mitochondrial dysfunction, hepatocellular carcinoma progression via macrophage phagocytosis regulation, and ALS motor neuron connectivity 6789. ESYT1 is also implicated in osteoarthritis lipid metabolism 10. These findings position ESYT1 as a critical regulator of membrane contact site dynamics with therapeutic potential across metabolic and neurodegenerative diseases.