Preparation and evaluation of N-acetylgalactosamine-modified hydroxypropyl-β-cyclodextrin as a potential therapeutic for MASLD/MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disorder characterized by lipid accumulationthat affects approximately 30% of the global population. MASLD is classified as simple steatosis or metabolic dysfunction-associated steatohepatitis (MASH), which can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. The excessive accumulation of free cholesterol in the liver is partially involved in the pathogenesis of MASH. Recently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has shown therapeutic potential in lipid storage disorders such as Niemann–Pick disease type C, owing to its cholesterol-lowering effect. Therefore, HP-β-CyD is considered a potential therapeutic agent for MASLD/MASH. In this study, to enhance liver accumulation and therapeutic potential of HP-β-CyD, we prepared N -acetylgalactosamine-modified HP-β-CyD (GalNAc-HP-β-CyD) to target the asialoglycoprotein receptor (ASGPR), which is highly expressed on the hepatocellular membrane. GalNAc-HP-β-CyD was taken up by hepatocytes via ASGPR-mediated endocytosis and accumulated in the liver with greater efficiency than HP-β-CyD. Furthermore, GalNAc-HP-β-CyD reduced free cholesterol levels in cholesterol-accumulated hepatocytes. These results suggest that GalNAc-HP-β-CyD has the potential to serve as a cholesterol-lowering agent for MASLD/MASH.