Polyguluronate sulfate has potential to mitigate hyperlipidemia by inhibiting the PCSK9-mediated degradation of LDLR

Hyperlipidemia has become a major global health challenge and one of the leading causes of mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating plasma protein, promotes the lysosomal degradation of hepatic low-density lipoprotein receptors (LDLR), thereby reducing the clearance of low-density lipoprotein (LDL) from blood plasma. PCSK9 has increasingly become a prominent therapeutic target for the development of lipid-lowering agents. In this study, we firstly identified polyguluronate sulfate (PGS) as a novel PCSK9 inhibitor. PGS could bind to the positively charged domain of PCSK9 with a KD value of 3.198 μM, effectively blocking its mediated LDLR degradation. This interaction leads to increase in LDLR levels on hepatocyte surface, enhancing LDL clearance. Furthermore, we demonstrated that PGS more effectively activates the AMP-activated protein kinase (AMPK) pathway compared to polymannuronate sulfate (PMS) at 200 μg/mL, resulting in about 2-fold greater lipid-lowering effect. In summary, our findings highlight PGS as a promising candidate for the development of novel lipid-lowering drugs, offering new insights into the therapeutic potential of sulfate polysaccharides targeting PCSK9.