C2CD2L is a lipid-binding protein that transports phosphatidylinositol from the endoplasmic reticulum (ER) to the plasma membrane, maintaining phosphoinositide pools critical for cellular signaling 1. It localizes to ER-plasma membrane contact sites where it tethers the two bilayers and coordinates calcium and phosphoinositide signaling 1. Upon cytosolic calcium elevation, C2CD2L undergoes C-terminal phosphorylation and dissociates from the membrane, halting phosphatidylinositol transport 1. This mechanism is essential for insulin secretion: phosphatidylinositol replenishment allows PI(4,5)P2 pool restoration and calcium channel opening, priming insulin granule exocytosis 1. C2CD2L forms protein complexes with band 4.1 family members at cell-cell contact sites, where its calcium-dependent shedding from the plasma membrane is suppressed, potentially supporting contact-dependent signaling 2. Clinically, C2CD2L emerges as a candidate therapeutic target in multiple diseases. It was identified as a core protein with druggability in diabetic nephropathy through mitochondrial proteomics and Mendelian randomization 3, and as a novel candidate protein associated with chr11 kidney disease 4. Additionally, C2CD2L functions as a biomarker for insomnia 5, shows association with postoperative delirium after cardiac surgery 6, and is implicated in triple-negative breast cancer progression through a miR-491-5p-dependent mechanism 7.