Magnolol attenuates hyperlipidemia-induced endothelial disorder by alleviating oxidative stress, inflammation, and mitochondrial dysfunction via p38 MAPK-FoxO1 axis.

Endothelial dysfunction (ED) is closely associated with hyperlipidemia and the pathogenesis of cardiovascular disease. Magnolol (MAG), an organic compound derived from the bark of the traditional Chinese medicinal herb Magnolia officinalis, has been reported to exhibit potent anti-inflammatory and antioxidant properties. Here, we demonstrate that MAG pretreatment ameliorates hyperlipidemia-induced ED, inflammation, oxidative stress, and mitochondrial dysfunction. Consistent results were observed in human aortic endothelial cells (HAECs). Combined with transcriptomic data, further investigations suggest that the p38 MAPK-FoxO1 signaling pathway mediates the protective effect of MAG on ED. Accordingly, validation experiments involving FoxO1 knockdown in HAECs, along with administration of the selective p38 MAPK inhibitor SB203580, confirmed that MAG regulates palmitic acid (PA)-induced cellular oxidative stress and mitochondrial dysfunction through a FoxO1- and p38 MAPK-dependent mechanism. Meanwhile, molecular docking results indicated that MAG can directly bind to FoxO1. Our study underscores the efficacy of MAG in alleviating vascular endothelial dysfunction and elucidates its underlying mechanisms. This work may lay the foundation for developing novel MAG-based therapeutic strategies for the clinical management of hyperlipidemia-related vascular complications.