Proprotein convertase subtilisin-kexin type 9 (PCSK9)

Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a secreted serine protease belonging to the peptidase S8 family[2][3][6]. PCSK9 is synthesized as an approximately 72-kDa precursor and undergoes autocatalytic cleavage, with its prodomain remaining associated during secretion[1][3][6]. Its major physiological role is in regulating plasma cholesterol levels: PCSK9 binds the epidermal growth factor-like repeat A (EGF-A) domain of the hepatic LDL receptor, targeting LDLR for lysosomal degradation and thus reducing hepatic LDL clearance from circulation[4][5][6][7]. Gain-of-function mutations in PCSK9 (such as D374Y) increase its affinity for LDLR and are linked to familial hypercholesterolemia and early-onset atherosclerosis[5][6]. Loss-of-function mutations result in hypocholesterolemia and protect against cardiovascular disease[3][7]. PCSK9 inhibitors, such as monoclonal antibodies (alirocumab, evolocumab) and siRNA drugs (inclisiran), are potent cholesterol-lowering agents used clinically to reduce cardiovascular risk[5][7]. PCSK9 also has expression and potential roles outside the liver, such as in the epidermis and central nervous system, but these are less well understood[2][3].

Other names

PCSK9NARC-1 (Neural apoptosis-regulated convertase 1)Proprotein convertase 9

Monoclonal antibodies (e.g., alirocumab, evolocumab) bind extracellular PCSK9, preventing its interaction with LDLR, thereby increasing LDLR recycling and hepatic uptake of LDL-C. siRNA (inclisiran) reduces PCSK9 protein synthesis, lowering its plasma levels and function.