Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis

作者：Yi Zhu, Jin Yang, Jiali Zhang, Hao Liu, Xue-jiao Yan, Jiyong Ge, Fangfang Wang · 发表于：Cellular Signalling · 年份：2025 · DOI：10.1016/j.cellsig.2025.111824 · 被引用次数：15 · 研究领域：Ferroptosis and cancer prognosis、MicroRNA in disease regulation、Cancer-related molecular mechanisms research

Vascular endothelial ferroptosis is a key mechanism underlying endothelial injury and atherosclerotic plaque formation. Dapagliflozin , an essential medication in the management of heart failure, has been shown to delay atherosclerosis progression. However, the underlying mechanisms remain unclear. This study aimed to elucidate the molecular pathways whereby dapagliflozin inhibits vascular endothelial ferroptosis . We utilized human umbilical vein endothelial cells (HUVECs) to construct a cell model of atherosclerosis combined with ferroptosis . Dapagliflozin significantly decreased the iron and malondialdehyde levels and the release of inflammatory factors in HUVECs treated with oxidized low-density lipoprotein or Erastin but increased the superoxide dismutase activity and the reduced glutathione / oxidized glutathione ratio. Results from transmission electron microscopy indicated that dapagliflozin alleviated the mitochondrial shrinkage and the reduction in the number of cristae in these HUVECs. RNA sequencing revealed that dapagliflozin upregulates RAP1B . In vitro experiments showed that RAP1B upregulates NRF2 and promotes its nuclear translocation, activating the xCT/GPX4 signaling pathway and inhibiting lipid peroxidation . Additionally, dapagliflozin induces mitochondrial biogenesis and enhances oxidative phosphorylation through the RAP1B/NRF2 pathway, reducing iron overload and excessive production of mitochondrial reactive oxygen species , ultimately mitigating ferro...