Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Regulation of Hepatic Triglyceride Metabolism

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulator of cholesterol homeostasis, primarily by promoting the lysosomal degradation of the hepatic low-density lipoprotein receptor (LDLR). However, emerging clinical and preclinical evidence suggests that PCSK9's influence extends beyond cholesterol clearance to the modulation of hepatic triglyceride metabolism. This review examines the biochemical mechanisms by which PCSK9 regulates intrahepatic triglyceride steady-state concentrations, highlighting its role in the assembly and lipidation of very low-density lipoproteins (VLDL) through both LDLR-dependent and independent mechanisms. We further discuss the integration of PCSK9 activity with hepatic lipid-sensing mechanisms and de novo lipogenesis. Finally, we evaluate the impact of current PCSK9-targeted therapies on the hepatic lipidome and contextualize these findings within the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). By highlighting the non-canonical roles of PCSK9, we aim to critically assess its potential as a multifaceted therapeutic target for dyslipidemias and steatotic liver diseases.