Low-density lipoprotein (LDL) particles are known to be atherogenic agents in coronary artery diseases. They adjust to other electronegative forms and can be the subject for the enhancement of inflammatory events in vessel subendothelial spaces. The LDL uptake is related to the membrane scavenger receptors, including LDL receptor (LDLR). The LDLR expression is closely associated with LDL uptake and occurrence of diseases, such as atherosclerotic cardiovascular diseases. Our findings identified USP16 as a novel regulator of LDLR due to its ability to prevent ubiquitylation-dependent LDLR degradation, further promoting the uptake of LDL. The enhancement of USP16-mediated deubiquitination and the suppressive degradation of the LDLR cause the presentation of a potential strategy to increase LDL cholesterol clearance.