Ellagic Acid and Its Nanoparticles Mitigate Atherosclerosis by Elevating Low‐Density Lipoprotein Receptor Levels Through Targeting of the Epidermal Growth Factor Receptor

ABSTRACT Atherosclerosis is a chronic vascular disease characterized by the accumulation of cholesterol‐rich lipids within the intima of large and medium‐sized arteries. It is a leading cause of morbidity and mortality worldwide, contributing to the majority of myocardial infarctions and strokes. Ellagic acid (EA), a naturally occurring polyphenolic compound found in various plant species, exhibits promising potential in enhancing cholesterol metabolism and reducing the risk of atherosclerosis. However, the precise mechanisms and molecular targets underlying EA's cholesterol‐regulating effects remain poorly understood. In this study, we demonstrate that EA effectively binds to the epidermal growth factor receptor (EGFR), exhibiting a dissociation constant (Kd) of 4.33 × 10 −7 M and a binding energy of −7.1 kcal/mol. This binding activates EGFR and specifically engages the mitogen‐activated protein kinase (MAPK) pathway, leading to the upregulation of low‐density lipoprotein receptor (LDLR) expression in HepG2 cells. Furthermore, cetuximab, an EGFR‐blocking antibody, inhibits the LDLR upregulation induced by EA, confirming EGFR as a key target in the regulation of LDLR expression. To evaluate the in vivo effects of EA on atherosclerosis, we encapsulated EA within human serum albumin to form nanoparticles (EA‐NPs). This approach addresses poor water solubility and its tendency to convert into urolithin derivatives of EA following oral administration. In HepG2 cells, EA‐NPs significantly enhanced LDLR expression, accompanied by increased phosphorylation of EGFR and extracellular signal‐regulated kinase (ERK). In an ApoE − / − mouse model, EA‐NPs exhibited potent anti‐atherosclerotic effects mediated through the EGFR and MAPK pathways. Additionally, EA‐NPs reduced hepatic lipid accumulation and attenuated the formation of aortic plaques. In conclusion, EA and its nanoparticle formulation effectively impede the progression of atherosclerosis, underscoring their therapeutic potential. These findings provide a robust foundation for the development of EA‐based strategies as a viable daily therapeutic intervention for atherosclerosis management.