PCSK9 (proprotein convertase subtilisin/kexin type 9) mRNA

Class

siRNA (GalNAc-conjugated RNAi therapeutic, subcutaneous)

Pathway

PCSK9 / LDL receptor recycling pathway

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a liver-secreted protein that regulates how much low-density lipoprotein (LDL) cholesterol is cleared from the bloodstream. It binds LDL receptors on the surface of liver cells and directs them toward degradation rather than recycling back to the cell surface. Fewer LDL receptors means less LDL is removed from circulation, so higher PCSK9 activity correlates with higher LDL cholesterol, a well-established driver of atherosclerotic cardiovascular disease. This mechanism uses small interfering RNA (siRNA), a class of RNA-based medicine that binds to a specific messenger RNA (mRNA) sequence and triggers its degradation inside the cell, preventing the corresponding protein from being made. Here the siRNA targets PCSK9 mRNA in liver cells, reducing PCSK9 protein production. With less PCSK9 available, LDL receptors persist longer on the cell surface, increasing LDL clearance and lowering circulating LDL cholesterol. The construct is chemically conjugated to N-acetylgalactosamine (GalNAc), a sugar molecule recognized by a receptor expressed almost exclusively on liver cells, which directs the drug preferentially to the liver after subcutaneous injection. This approach broadly matters in cardiovascular disease prevention, where sustained LDL lowering is a central therapeutic goal.