PCSK9

Class

PCSK9-targeted therapeutic

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein secreted mainly by the liver that regulates how many low-density lipoprotein receptors (LDLRs) appear on the surface of liver cells. LDLRs are responsible for pulling LDL cholesterol ('bad cholesterol') out of the bloodstream. Normally, after an LDLR captures a cholesterol particle, it recycles back to the cell surface to work again. PCSK9 binds to the LDLR and redirects it toward destruction instead, reducing the number of receptors available and leaving more LDL cholesterol circulating in blood. People with naturally occurring PCSK9 loss-of-function variants have lifelong low LDL cholesterol and reduced rates of atherosclerotic cardiovascular disease, while gain-of-function variants cause a hereditary form of very high cholesterol. This genetic evidence established PCSK9 as a rational drug target: blocking its activity or reducing its production allows more LDLR to persist, increasing clearance of LDL cholesterol from the blood. Because elevated LDL cholesterol is a major driver of atherosclerosis, heart attack, and stroke, PCSK9-targeted therapies are used, often alongside other cholesterol-lowering treatments, to bring LDL cholesterol down further in people at cardiovascular risk.