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Diabetic retinopathy (DR) is one of the most serious complications of diabetic microangiopathy. Recent studies have shown its close association with high glucose-induced oxidative stress and autophagy disorder. Previous studies showed that various compounds of flavonoids of Sophora flavescens Aiton extracted using ethyl acetate (SFE) could cross the blood-retinal barrier, exerting favorable effects on retinal tissue disorders and angiogenesis in rats with DR. However, the mechanism and the specific material basis for SFE are still unclear. Here, we established the in vitro DR model of human retinal microvascular endothelial cell (HRMECs) induced by high glucose and hypoxia (HGY), screened out the potential pharmacodynamic components of SFE viz. norkurarinone (NKR) and isoxanthohumol (IXM), and proved that they could improve the pathological features of angiogenesis. Further, we explored the mechanism of action of NKR and IXM, investigating their effects on cellular oxidative stress and autophagy levels under HGY conditions. Finally, the role of the PI3K/AKT/mTOR signaling pathway in the regulation of cell autophagy by NKR and IXM was evaluated. Collectively, NKR and IXM could improve cellular oxidative stress state and activate PI3K/AKT/mTOR signaling pathway to regulate autophagy dysregulation, thus playing a significant role in protecting HRMECs from HGY-caused angiogenesis. • Screening out the potential pharmacodynamic components of SFE viz. NKR and IXM. • NKR and IXM alleviated the angiogenesis of HRMECs induced by high glucose and hypoxia. • NKR and IXM improved oxidative stress of HRMECs induced by high glucose and hypoxia. • NKR and IXM activated the PI3K/AKT/mTOR signaling pathway to regulate autophagy. [ABSTRACT FROM AUTHOR]