PCSK9 is a crucial regulator of cholesterol homeostasis that binds to low-density lipoprotein receptor family members and promotes their degradation in intracellular acidic compartments. The protein acts through a non-proteolytic mechanism to enhance hepatic LDLR degradation via clathrin-mediated pathways, preventing receptor recycling and directing receptors to lysosomes for destruction 1. PCSK9 can induce LDLR ubiquitination and subsequent degradation, while circulating PCSK9 binds to apolipoprotein B100 on LDL particles, creating negative feedback regulation 1. Beyond cholesterol metabolism, PCSK9 regulates neuronal apoptosis through modulation of LRP8/APOER2 levels and inhibits epithelial sodium channel-mediated absorption. Recent evidence suggests PCSK9 may disrupt MHC class I recycling to the cell surface, promoting its lysosomal degradation and affecting immune responses 2. Gain-of-function mutations cause familial hypercholesterolemia, while loss-of-function variants protect against atherosclerotic cardiovascular disease 3. Multiple FDA-approved PCSK9 inhibitors including alirocumab, evolocumab, and inclisiran effectively reduce LDL cholesterol by 40-70% 3 4. These therapies demonstrate clinical benefit beyond lipid reduction through anti-inflammatory effects and improved endothelial function 5. Emerging applications include cancer immunotherapy, where PCSK9 inhibition enhances anti-PD1 therapy efficacy 2, though recent studies indicate potential increased osteoporosis risk 6.