Forsythoside B and Its Derivatives as Novel ASGR1 Inhibitors for Enhanced Cholesterol Efflux

The asialoglycoprotein receptor 1 (ASGR1), a hepatocyte-specific endocytic receptor, has recently emerged as a pivotal therapeutic target for metabolic diseases due to its critical role in regulating cholesterol efflux. Forsythoside B (FB), a naturally occurring phenylethanoid glycoside, has demonstrated lipid-modulating properties in previous studies. However, how it interacts with ASGR1-mediated cholesterol regulation remains unexplored. In this study, we systematically evaluated FB and its derivatives as novel ASGR1 inhibitors, focusing on their ability to promote cholesterol efflux in Huh-7 cells. Among the tested compounds, FB and its seven derivatives significantly enhanced cholesterol efflux in a concentration-dependent manner without affecting cell viability. Mechanistic studies revealed that these compounds exert their effects by inhibiting ASGR1. The findings of this study provide promising candidate molecules and establish a theoretical foundation for potential development of ASGR1-targeted cholesterol-lowering therapeutics.