Octyl gallate attenuates atherosclerosis by modulating PPARγ-associated cholesterol homeostasis and enhancing...

Atherosclerosis (AS) is a vascular disease driven by dysregulated lipid metabolism, oxidative stress, and chronic inflammation. This study investigated the anti-atherosclerotic potential of octyl gallate (OG), a gallic acid derivative with anti-inflammatory and metabolic regulatory properties. In vitro, OG (20-50 μM) significantly attenuated oxidised low-density lipoprotein (ox-LDL)-induced lipid accumulation in THP-1-derived macrophages. This effect was accompanied by increased expression of the cholesterol efflux-related genes ABCA1 and ABCG1, whereas OG had only limited effects on CD36 and SRA expression. In vivo, oral administration of OG (25 or 50 mg kg^-1) for 3 months reduced atherosclerotic lesion formation in the aortic arch, whole aorta and aortic root of high-fat diet-fed Apoe^-/- mice. OG also improved serum lipid profiles by reducing low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels, increasing high-density lipoprotein cholesterol (HDL-C) levels. In addition, OG decreased IL-1β and TNF-α expression in the aortic root. Network pharmacology, molecular docking and molecular dynamics simulations identified PPARγ as a potential molecular target of OG. Further experiments demonstrated that OG enhanced the expression of PPARγ, LXRα, ABCA1, and ABCG1 in ox-LDL-treated macrophages. Moreover, OG suppressed inflammatory responses and reactive oxygen species (ROS) accumulation while activating the NRF2-NQO11 antioxidant system and promoting NRF2 nuclear translocation. Collectively, these findings suggest that OG may exert anti-atherosclerotic effects by coordinating macrophage lipid metabolism, redox homeostasis, and inflammatory responses through the PPARγ-LXRα-ABCA1/ABCG1 axis and the NRF2-NQO1 antioxidant pathway, respectively. These results provide experimental evidence supporting the potential of OG as a candidate compound for the prevention and treatment of AS.