Fisetin-loaded nanoparticles as a novel approach for cholesterol regulation in hypercholesterolemia: targeting the ASGR1-mediated mTORC1/AMPK pathway.

Hypercholesterolemia is a major risk factor for the development of atherosclerotic cardiovascular disease. The flavonoid fisetin shows potential cholesterol-regulating effects. Nevertheless, poor solubility and low bioavailability limit its clinical application. This study investigates fisetin's effects on hypercholesterolemia and underlying mechanisms. Using a hypercholesterolemic mouse model, we observe that fisetin significantly attenuates hepatic steatosis, decreases total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, and alleviates oxidative stress. Consistent results are observed in cellular experiments. Fisetin administration markedly modulates hepatic proteins involved in cholesterol excretion (ABCA1, ABCG5, ABCG8, CYP7A1, and LXRα) and cholesterol metabolism (HMGCR, LDLR, and SR-B1), thereby maintaining cholesterol homeostasis. Mechanistically, fisetin targets asialoglycoprotein receptor 1 (ASGR1), modulating the mTORC1/AMPK-BRCA1/BARD1 pathway. Notably, ASGR1 overexpression counteracts fisetin's cholesterol-lowering effects. Additionally, carboxymethyl chitosan (CMCS)-modified β-cyclodextrin (β-CD)-based fisetin nanoparticles notably reduce lipid accumulation, TC and TG levels, even at concentrations one-fifth of free fisetin. In summary, fisetin effectively modulates cholesterol metabolism and represents a promising therapeutic approach for managing hypercholesterolemia. The fisetin nanoparticles offer an innovative strategy to overcome fisetin's clinical limitations, enhancing its bioavailability and therapeutic efficacy.