C2CD2L is a lipid-binding protein that transports phosphatidylinositol from the endoplasmic reticulum (ER) to the plasma membrane, thereby replenishing phosphoinositide pools consumed during phospholipase C signaling. The protein localizes to ER–plasma membrane contact sites, where it tethers the two bilayers and coordinates calcium and phosphoinositide signaling. Upon elevation of cytosolic calcium, C2CD2L is phosphorylated at its C-terminus and dissociates from the membrane, halting phosphatidylinositol transfer. This regulatory mechanism is particularly important in neurons, where C2CD2L levels increase during neuronal differentiation and the protein populates ER–PM contacts enriched in ion channels. In pancreatic β-cells, C2CD2L positively regulates insulin secretion by enabling phosphatidylinositol replenishment and calcium channel opening, thereby priming insulin granule release in response to glucose. C2CD2L has been associated with multiple clinical conditions, including chr11 kidney disease and diabetic nephropathy, where it has emerged as a candidate therapeutic target through Mendelian randomization analyses 1 2. Recent evidence also implicates C2CD2L in postoperative delirium, where it ranks among the top differentially expressed biomarkers in affected patients 3, and in triple-negative breast cancer progression through microRNA-mediated regulation 4. Additionally, C2CD2L has genetic associations with alcohol consumption and forms specialized complexes with band 4.1 proteins at cell–cell contacts 5 6.