What does this research mean for the field?

Fisetin-loaded nanoparticles effectively reduce total cholesterol, triglycerides, and LDL cholesterol levels in hypercholesterolemic mice by modulating cholesterol metabolism pathways. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

To investigate fisetin’s effects on cholesterol regulation and the underlying mechanisms in hypercholesterolemia.

March 1, 2026Open Access

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

Key Points

To investigate fisetin’s effects on cholesterol regulation and the underlying mechanisms in hypercholesterolemia.
Used a hypercholesterolemic mouse model
Administered fisetin and analyzed its impact on lipid levels
Examined hepatic proteins involved in cholesterol metabolism
Developed fisetin-loaded nanoparticles to enhance bioavailability
Fisetin significantly reduced total cholesterol, triglycerides, and LDL-C levels
Attenuated hepatic steatosis and oxidative stress
Fisetin modulated key hepatic proteins related to cholesterol metabolism
ASGR1 overexpression blocked fisetin's cholesterol-lowering effects
Fisetin nanoparticles reduced lipid accumulation at lower concentrations than free fisetin

Abstract

Abstract 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. Graphical abstract

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Cite This Study

Zhang et al. (Fri,) studied this question.

synapsesocial.com/papers/69a3d89aec16d51705d2f861 https://doi.org/https://doi.org/10.1186/s12951-026-04181-z

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