Wedelolactone Ameliorates Ischemic Stroke by Inhibiting Oxidative Damage and Ferroptosis via HIF-1α/SLC7A11/GPX4 Signaling

作者：Xingru Tao, Meina Zhao, Kai Gao, Wei Zhang, Dong Xu, Wangting Li, Fei Mu, Rui Lin, Chao Guo, Ruili Li, Jingwen Wang · 发表于：Drug Design Development and Therapy · 年份：2025 · DOI：10.2147/dddt.s528831 · 被引用次数：9 · 研究领域：Ferroptosis and cancer prognosis、Neuroinflammation and Neurodegeneration Mechanisms、Cholesterol and Lipid Metabolism

Purpose: Wedelolactone (Wel), a furocoumarin compound extracted from the medicinal plant Eclipta prostrata L . has been shown to exhibit significant neuroprotective effects. However, the potential of Wel to improve ischemic stroke (IS) and the underlying mechanisms remain unclear. Methods: The middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) were established to evaluate the potential neuroprotective of Wel. Neurological function, brain infarct volume, brain swelling, and histopathological staining were analyzed to demonstrate the therapeutic efficacy of Wel. The occurrence of ferroptosis was confirmed by quantifying the levels of ROS and Fe 2+ , and by examining the ultrastructural features of cells. The binding affinity between Wel and HIF-1α was evaluated using Molecular docking. Immunofluorescence and Western blot analyses were conducted to explore the regulation of Wel on the HIF-1α/SLC7A11/GPX4 pathway. Finally, the expression of HIF-1α was down-regulated to verify whether Wel exerts neuroprotection by modulating HIF-1α to inhibit ferroptosis of cells. Results: The results demonstrated that Wel effectively inhibit neuron ferroptosis after MCAO/R in a dose-time-dependent manner, thereby alleviating brain injury. Moreover, at the cellular level, Wel significantly reduced the accumulation of Fe 2+ and ROS after OGD/R. Further investigation revealed that Wel might inhibit neuronal ferroptosis and improve IS by pro...