FHCL3, EC 3.4.21, EC, Neural apoptosis-regulated convertase 1, Proprotein convertase 9, NARC1, PSEC0052, PCSK9, NARC-1, EC:3.4.21.-, Proprotein Convertase Subtilisin/Kexin Type 9, Subtilisin/Kexin-Like Protease PC9, PC9, Convertase Subtilisin/Kexin Type 9 Preproprotein, Hypercholesterolemia, Autosomal Dominant 3, EC 3.4.21.-, HCHOLA3, LDLCQ1, FH3, Neural Apoptosis Regulated Convertase 1


Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It plays a crucial role in regulating plasma cholesterol homeostasis. It binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. It acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway and may prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. It can induce ubiquitination of LDLR leading to its subsequent degradation and inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. It is involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. It inhibits epithelial Na+ channel (ENaC)-mediated Na+ absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation and regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.

KO Status

F1 (+/-)

Drug Information

Launched drugs: 2
Drugs in clinical trials: 16
Latest Research Phase: Approved

Drug Name





Clinical Trials

Inclisiran sodium

ALN-60212, PCSK9si, ALN-PCSsc, KJX839, KJX-839


Alnylam Pharmaceuticals Inc

Plaque, Atherosclerotic, Homozygous familial hypercholesterolemia, Atherosclerosis, Diabetes Mellitus, Type 2, Hypercholesterolemia, Kidney Diseases, Hypolipoproteinemias, Dyslipidemias, Diabetes Mellitus, Hyperlipoproteinemia Type II, Hyperlipidemias


316P, REGN-727, SAR-236553


Sanofi, Regeneron Pharmaceuticals Inc

Homozygous familial hypercholesterolemia, Atherosclerosis, Hypercholesterolemia, Acute Coronary Syndrome, Dyslipidemias, Hyperlipoproteinemia Type II




Amgen Inc, Astellas Pharma Inc

Homozygous familial hypercholesterolemia, Myocardial Infarction, Diabetes Mellitus, Type 2, Atherosclerosis, Hypercholesterolemia, Coronary Artery Disease, Stroke, Coronary Disease, Dyslipidemias, Cardiovascular Diseases, Diabetes Mellitus, Hyperlipidemias, Hyperlipoproteinemia Type II



Phase 3 Clinical

Shanghai Junshi Biosciences Co Ltd

Hypertriglyceridemia, Atherosclerosis, Hypercholesterolemia, Hyperlipidemia, Familial Combined, Hyperlipidemias



Phase 3 Clinical

Lib Therapeutics

Hypercholesterolemia, Stroke, Cardiovascular Diseases, Hyperlipoproteinemia Type II



Phase 3 Clinical

Innovent Biologics(Suzhou) Co Ltd

Homozygous familial hypercholesterolemia, Hypercholesterolemia


CiVi-007, LNA-PCSK -9, LNA-PCSK9-GalNac

Phase 2 Clinical

F. Hoffmann-La Roche Ltd




Phase 2 Clinical

Zhongshan Akeso Biopharma Co Ltd, Yabao Us Pharmaceutical Co Ltd

Homozygous familial hypercholesterolemia, Hypercholesterolemia, Hyperlipidemias, Hyperlipoproteinemia Type II


C-8304, CVI-LM001

Phase 2 Clinical

Xiwei'Ai Medicine Technology (Shanghai) Co Ltd

Hypercholesterolemia, Hyperlipidemias



Phase 2 Clinical

Jiangsu Hengrui Medicine Co Ltd

Hypercholesterolemia, Hyperlipidemias, Hyperlipoproteinemia Type II





The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation

Seidah N.G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S.B., Stifani S., Basak A., Prat A., Chretien M.,

Proc. Natl. Acad. Sci. U.S.A. 100:928-933(2003)

Functional characterization of Narc 1, a novel proteinase related to proteinase K

Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C.F., Huang Y., Chiang L.W., Grenier J.M., Ozenberger B.A., Jacobsen J.S., Kennedy J.D., DiStefano P.S., Wood A., Bingham B.,

Arch. Biochem. Biophys. 420:55-67(2003)

Global, in vivo, and site-specific phosphorylation dynamics in signaling networks

Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.,

Cell 127:635-648(2006)

The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications

Benjannet S., Rhainds D., Hamelin J., Nassoury N., Seidah N.G.,

J. Biol. Chem. 281:30561-30572(2006)

The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR

Nassoury N., Blasiole D.A., Tebon Oler A., Benjannet S., Hamelin J., Poupon V., McPherson P.S., Attie A.D., Prat A., Seidah N.G.,

Traffic 8:718-732(2007)

Self-association of human PCSK9 correlates with its LDLR-degrading activity

Fan D., Yancey P.G., Qiu S., Ding L., Weeber E.J., Linton M.F., Fazio S.,

Biochemistry 47:1631-1639(2008)

PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1

Jonas M.C., Costantini C., Puglielli L.,

EMBO Rep. 9:916-922(2008)

PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans

Dewpura T., Raymond A., Hamelin J., Seidah N.G., Mbikay M., Chretien M., Mayne J.,

FEBS J. 275:3480-3493(2008)

The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2

Poirier S., Mayer G., Benjannet S., Bergeron E., Marcinkiewicz J., Nassoury N., Mayer H., Nimpf J., Prat A., Seidah N.G.,

J. Biol. Chem. 283:2363-2372(2008)

Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels

Mayer G., Poirier S., Seidah N.G.,

J. Biol. Chem. 283:31791-31801(2008)