Acacetin Attenuates Atherosclerosis Through Coordinated Regulation of NF-κB-Driven Inflammation and FOXO3a-Mediated Antioxidant Defense in Macrophages.

Abstract

PURPOSE: This study aimed to investigate the mechanisms by which acacetin alleviates atherosclerosis via AKT-mediated regulation of FOXO3a and NF-κB signaling in macrophages. METHODS: Network pharmacology, Gene Expression Omnibus (GEO) database analysis, and machine learning were integrated to identify the potential core targets of acacetin against atherosclerosis. Target engagement was further validated using molecular docking, molecular dynamics simulations, and Cellular Thermal Shift Assay (CETSA). In vitro, the effects of acacetin on M1-associated inflammatory activation and oxidative stress were investigated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages using qRT-PCR, Western blotting, immunofluorescence, and biochemical assays and siRNA-mediated AKT1 knockdown to confirm target specificity. In vivo, the progression of atherosclerotic lesions and the regulation of key signaling pathways were assessed in high-fat diet-fed ApoE-/- mice through histological staining, immunohistochemistry, and Western blot analysis. RESULTS: AKT1 was identified as a core target of acacetin against atherosclerosis. Functionally, acacetin attenuated M1-associated inflammatory activation in vitro and reduced atherosclerotic lesion development and lipid deposition, while promoting features associated with plaque stabilization in ApoE-/- mice. Mechanistically, acacetin inhibited AKT-mediated NF-κB activation, suppressing pro-inflammatory mediators including iNOS and IL-1β, while promoting FOXO3a nuclear localization and upregulating SOD2-dependent antioxidant defense. CONCLUSION: Acacetin alleviates atherosclerosis by modulating AKT-mediated signaling to concurrently suppress NF-κB-driven inflammation and restore FOXO3a-mediated antioxidant defense in macrophages.

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