Mecanismos de acción de la acacetina en la supresión de la aterosclerosis: vía de señalización de la ferroptosis...

Acacetin, a natural flavonoid compound, exhibits anti-inflammatory, antioxidant, and lipid-lowering properties, indicating promising therapeutic potential for the prevention and treatment of cardiovascular diseases (CVD). However, the mechanisms underlying its therapeutic effects on atherosclerosis (AS) remain incompletely understood. This study aims to systematically elucidate the role and molecular mechanisms of Acacetin in the pathological progression of AS. First, network pharmacology was employed to predict the potential therapeutic targets of Acacetin in combating AS. Subsequently, both in vivo and in vitro experiments were established to investigate the underlying mechanisms. The in vivo AS model was generated by feeding apolipoprotein E knockout (ApoE^-/-) mice a high-fat diet (HFD), while the in vitro pathological model involved stimulating human umbilical vein endothelial cells (HUVECs) with Human Angiotensin II (AngII). Experimental results demonstrated that Acacetin treatment significantly improved abnormal lipid metabolism in mice and effectively inhibited oxidative stress. Regarding pathological changes, Acacetin reduced aortic lipid accumulation and plaque formation in mice and significantly downregulated p53 protein expression in the aortic root. Further mechanistic studies confirmed that Acacetin targets the HDAC4-p53 signaling pathway. By modulating the acetylation status of p53, Acacetin inhibits cellular ferroptosis and prevents apoptosis, thereby exerting anti-AS effects. Moreover, co-immunoprecipitation (CO-IP) assays and small interfering RNA targeting HDAC4 (si-HDAC4) intervention experiments demonstrated a direct interaction between HDAC4 and p53, further validating the specificity of this pathway. In conclusion, this study elucidates that Acacetin exerts anti-AS effects through the HDAC4-p53 pathway, providing a robust theoretical foundation and experimental evidence to support its potential clinical application.