Ginkgolide B attenuates hyperlipidemia by restoring sphingolipid homeostasis and activating PPARα and Nrf2 pathways

Although hyperlipidemia is a key factor in cardiovascular disease, there are limited safe and effective therapies for disorders of lipid metabolism. This study investigated the therapeutic potential of Ginkgolide B (GB), a bioactive component of Ginkgo biloba leaves, in ameliorating hyperlipidemia and explored its underlying mechanisms. Utilizing a high-fat diet-induced hyperlipidemic rat model and lipidomics analysis, the study showed that GB significantly decreased serum total cholesterol, triglyceride, and low-density lipoprotein levels. Lipidomics revealed that GB reversed dysregulated sphingolipid metabolism, notably decreasing ceramides levels and increasing sphingomyelins, which are implicated in metabolic inflammation and oxidative stress. Mechanistically, GB activated PPARα, thereby enhancing fatty acid oxidation and upregulating the Nrf2 pathway to mitigate oxidative damage. These dual effects were validated in vitro using HepG2 cells, where GB reduced lipid accumulation and improved antioxidant defenses. Overall, these findings highlight GB as a promising therapeutic agent for hyperlipidemia by restoring sphingolipid homeostasis and targeting the interplay between lipid metabolism and oxidative stress.