Ellagic acid ameliorates atherosclerosis by inhibiting PCSK9 through the modulation of FoxO3 and HNF1α

Proprotein convertase subtilisin/kexin type 9 (PCSK9) hinders the clearance of low-density lipoprotein cholesterol (LDL-C) by promoting the degradation of the low-density lipoprotein receptor (LDLR), leading to the accumulation of LDL-C and thus becoming an important cause of atherosclerosis. Ellagic acid, a naturally occurring polyphenol widely present in fruits, vegetables, and nuts, has attracted significant attention due to its potential role in the prevention and treatment of cardiovascular diseases. However, the molecular mechanisms by which ellagic acid alleviates atherosclerosis by inhibiting PCSK9 are not fully understood.

This study further validated the mechanism of action of ellagic acid through in vitro HepG2 cell experiments and a high-fat diet-induced ApoE^-/- mouse model.

The results showed that ellagic acid significantly reduced the expression and secretion of PCSK9 while upregulating LDLR protein levels; its mechanism is related to the inhibition of hepatocyte nuclear factor 1α (HNF1α) expression and the promotion of forkhead box O3 (FoxO3) expression increase. Additionally, ellagic acid reduced aortic plaque deposition in mice induced by a high-fat diet; consistent with the in vitro experimental results, ellagic acid lowered the expression and secretion of PCSK9 and elevated LDLR protein levels by inhibiting HNF1α and increased FoxO3 expression.

In summary, this study demonstrates that ellagic acid inhibits PCSK9 by regulating HNF1α and FoxO3, thereby increasing LDLR levels and alleviating atherosclerosis. This finding not only consolidates the scientific basis of plant-based diets for preventing cardiovascular diseases but also provides an important direction for developing functional foods and nutritional intervention strategies based on natural polyphenols.