Ginkgolide C alleviates atherosclerosis via activating Nrf2 to inhibit ROS‑dependent NLRP3 inflammasome activation.

Atherosclerosis (AS), a chronic vascular pathology characterized by endothelial dysfunction, arises from the interplay of lipid dysregulation, oxidative stress, and inflammatory activation. Reactive oxygen species (ROS) overproduction triggers Nod‑like receptor protein 3 (NLRP3) inflammasome signaling, exacerbating inflammatory cascades that drive plaque progression. The nuclear factor erythroid 2‑related factor 2 (Nrf2)‑mediated antioxidant pathway serves as a critical counterbalance to ROS/NLRP3 axis dysregulation, positioning pharmacological Nrf2 activation as a promising therapeutic strategy. The present study investigated the anti‑atherosclerotic potential of ginkgolide C (GC), a terpene lactone from Ginkgo biloba with established anti‑inflammatory and anti‑ischemia/reperfusion injury properties, through coordinated modulation of redox‑inflammatory pathways. Complementary in vivo (high‑fat diet/vitamin D3‑treated ApoE-/- mice) and in vitro (oxidized‑low density lipoprotein‑stimulated aortic endothelial cells) models were established. Comprehensive analyses included histopathological characterization, lipid profiling, ultrastructural examination, redox‑inflammatory biomarker quantification, and molecular pathway validation. GC significantly attenuated hyperlipidemia and plaque progression while preserving vascular ultrastructure. Mechanistically, GC enhanced endothelial survival through dual pathway modulation: i) Nrf2 nuclear translocation upregulated antioxidant enzymes [heme oxygenase‑1/NAD(P)H quinone oxidoreductase 1/glutamate‑cysteine ligase modifier subunit], restoring redox homeostasis; ii) NLRP3 inflammasome inhibition via Caspase‑1 suppression mitigated inflammatory cytokine release. The present study demonstrated GC's dual‑target therapeutic efficacy against AS through Nrf2‑mediated oxidative stress resolution and NLRP3 inflammasome inactivation, offering new insights into phytochemical‑based cardiovascular interventions.