Shikonin alleviates high-fat diet-induced vascular aging and dysfunction by inhibiting oxidative stress and mitochondrial damage.

BACKGROUND: Vascular aging and dysfunction are key contributors to the development of atherosclerosis, particularly under metabolic stress conditions such as high-fat diet (HFD). This study aimed to investigate the protective effect of the natural naphthoquinone compound shikonin (SKN) against HFD-induced vascular injury and to elucidate the underlying mechanisms. METHODS AND RESULTS: Male Sprague Dawley rats were fed a HFD for 10 consecutive weeks to induce metabolism-related vascular injury. From the fourth week onward, SKN was administered via intraperitoneal injection for 7 weeks. Endothelium-dependent vasodilation was assessed by acetylcholine-induced vascular reactivity. Histological changes in the aorta were examined using H&E, Masson’s trichrome, and Oil Red O staining. Oxidative stress markers, including ROS, MDA, GSH, SOD, and NADPH, were measured. Protein expression levels of NOX2, NOX4, P-p53, p21, DRP1, and FIS1 were detected by immunofluorescence and Western blotting. SKN significantly improved endothelial function and reduced collagen deposition and lipid accumulation in the aorta of HFD-fed rats. It also decreased NOX2/NOX4 expression, reduced MDA levels, and elevated GSH, SOD, and NADPH, indicating restored redox balance. Additionally, SKN downregulated vascular senescence markers (P-p53, p21) and mitochondrial fission proteins (DRP1, FIS1), suggesting attenuation of mitochondrial dysfunction and vascular aging. CONCLUSION: SKN alleviates HFD-induced vascular dysfunction and senescence by suppressing NOX-mediated oxidative stress and modulating mitochondrial dynamics, highlighting its therapeutic potential in metabolic vascular diseases.