NPC1L1 is a polytopic transmembrane protein that plays a critical role in cholesterol homeostasis by mediating the uptake of dietary cholesterol across the apical membrane of intestinal enterocytes 1. This process occurs through clathrin-mediated endocytosis and is regulated by cellular cholesterol content 1. Beyond cholesterol, NPC1L1 transports plant sterols such as sitosterol, though at lower efficiency [UniProt]. The protein also negatively regulates NPC2 by inhibiting its maturation and accelerating degradation [UniProt]. NPC1L1 is the direct molecular target of ezetimibe, an FDA-approved cholesterol absorption inhibitor 1, making it pharmaceutically relevant for treating hypercholesterolemia 2. Recent evidence reveals that downstream of NPC1L1, the Aster pathway mediates nonvesicular cholesterol transport in enterocytes, with NPC1L1 loss abolishing Aster recruitment to the brush border 3. Additionally, NPC1L1 expression is suppressed by immune-mediated pathways involving IL-10 signaling, linking gut immunity to intestinal cholesterol metabolism and atherosclerosis prevention 4. Loss of NPC1L1 function reduces cholesterol absorption and protects against diet-induced hypercholesterolemia 5, positioning it as a key target for cardiovascular disease prevention.