PCSK9 (gene and therapeutic target)

PCSK9 is both a gene and a hot drug target for lowering cholesterol. The protein (a serine protease made by your liver) latches onto the LDL receptor and sends it to be destroyed instead of recycled. Fewer receptors means your cells pull in less LDL, so blood LDL goes up. Genetics proved the target. Rare 'gain-of-function' PCSK9 mutations cause inherited high cholesterol. Rare 'loss-of-function' variants (common in African-American cohorts, like Y142X and C679X) give lifelong very low LDL and much lower heart-disease risk, with no downside. Drugs followed. Antibodies against PCSK9 (alirocumab, evolocumab) cut LDL by 50 to 60% on top of statins and lower event rates in high-risk patients. Inclisiran, a small-interfering RNA that silences PCSK9 in the liver, gets similar lowering with just twice-a-year dosing. And oral PCSK9 blockers like MK-0616 (enlicitide, from Merck) reached late-stage trials, with Phase 3 LDL results in 2024 to 2025; the cardiovascular-outcomes trial (CORALreef Outcomes) is still pending.

Last reviewed: June 22, 2026

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