Abstract : Oxidative stress-mediated endothelial cell injury is an important pathological mechanism underlying cardiovascular diseases. Natural flavonoids exhibit potent antioxidant activity. This study optimized the preparation process of Actinidia arguta flavonoid extract-loaded liposomes (AAFE-LIPS) and investigated their protective effects and potential mechanisms against H?O?-induced oxidative injury in human coronary artery endothelial cells (HCAECs). A Box–Behnken design (BBD) response surface methodology was used to optimize the formulation. An H?O?-induced HCAEC injury model was established to evaluate cell viability, oxidative stress, apoptosis, and the expression of related signaling proteins by Western blotting. The optimal preparation conditions were a soybean lecithin-to-cholesterol mass ratio of 7:1, a stirring temperature of 60 °C, and a stirring time of 45 min, yielding an encapsulation efficiency of 85.12%. After 24 h of pretreatment, 0.6 mg·mL?¹ AAFE-LIPS exhibited a pronounced protective effect against H?O?-induced HCAEC injury, with cell viability reaching 75.11%. AAFE-LIPS reduced apoptosis and intracellular ROS and MDA levels, increased GSH levels and SOD and CAT activities, promoted NO production, improved ATP levels, and decreased ET-1 expression. Western blot analysis showed that AAFE-LIPS downregulated the expression of Keap1, NF-κB, cleaved caspase-3, and ET-1, while upregulating Nrf2 and HO-1 expression. In conclusion, AAFE-LIPS exerted protective effects against H?O?-induced oxidative injury in HCAECs. These findings suggest that its protective effects may be associated with the regulation of proteins related to oxidative stress, inflammation, and apoptosis.