The discovery of novel, targeted cholesterol-lowering agents holds clinical value for cardiovascular disease (CVD) prevention and management. Here, we report the isolation of a naturally occurring polyketide, enterocin, from the marine-derived Streptomyces sp. FXY-T25 using a cholesterol-modulating activity-guided assay. Enterocin, with a unique tricyclic caged core skeleton, enhanced cholesterol efflux in Huh-7 and HepG2 liver cells by directly binding to ASGR1 and promoting its proteasomal degradation without transcriptional alteration. This ASGR1 inhibition triggered AMPKα activation and subsequent LXRα-mediated upregulation of cholesterol efflux. The accelerated degradation of ASGR1 was confirmed to be proteasome-dependent, as evidenced by lysosomal or proteasomal inhibitors. In high-fat-diet (HFD)-fed wild-type mice, enterocin significantly reduced visceral and subcutaneous fat, improved serum lipid profiles (decreasing TC, TG, and LDL-C while elevating HDL-C), attenuated hepatic lipid accumulation, and enhanced fecal cholesterol excretion. Consistent with the in vitro findings, enterocin downregulated hepatic ASGR1 protein levels and subsequently activated the AMPKα-LXRα-ABCA1/G1/G5/G8 pathway in mouse liver. In HFD-fed LDLRmice, enterocin exhibited lipid-lowering activity comparable or superior to that of the positive controls atorvastatin and GW3965. Notably, enterocin demonstrated no significant effect on intestinal fat absorption, highlighting its targeted activity in hepatic cholesterol metabolism. These findings establish enterocin as a novel therapeutic candidate that uniquely modulates cholesterol homeostasis, offering potential for the treatment of both hypercholesterolemia and metabolic dysfunction-associated fatty liver disease. -/-
