PCSK9 (gene and therapeutic target)

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease secreted by hepatocytes that binds to the LDL receptor on the cell surface and directs it to lysosomal degradation rather than recycling, thereby reducing LDL uptake and raising circulating LDL-cholesterol. Rare gain-of-function PCSK9 mutations cause familial hypercholesterolaemia, while loss-of-function variants — particularly prevalent in African-American cohorts (e.g., Y142X, C679X) — produce lifelong very low LDL levels and markedly reduced coronary heart disease risk without adverse phenotypes, validating the target. Monoclonal antibodies against PCSK9 (alirocumab, evolocumab) reduce LDL by 50–60% on top of statin therapy and lower cardiovascular event rates in high-risk patients; inclisiran, a small-interfering RNA targeting PCSK9 mRNA in hepatocytes, achieves similar LDL lowering with twice-yearly dosing.