Accumulating evidence of the critical role of Ferrostatin-1 (Fer-1, ferroptosis inhibitor) in cerebral ischemia has intrigued us to explore the molecular mechanistic actions of Fer-1 delivery by bone marrow mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) in cerebral ischemia-reperfusion (I/R) injury. In vivo middle cerebral artery occlusion (MCAO) in mice and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) in hippocampal neurons were developed to simulate cerebral I/R injury. After Fer-1 was confirmed to be successfully delivered by MSCs-EVs to neurons, we found that MSCs-EVs loaded with Fer-1 (MSCs-EVs/Fer-1) reduced neuron apoptosis and enhanced viability, along with curtailed inflammation and ferroptosis. The regulation of Fer-1 on GPX4/COX2 axis was predicted by bioinformatics study and validated by functional experiments. The in vivo experiments further confirmed that MSCs-EVs/Fer-1 ameliorated cerebral I/R injury in mice. Furthermore, poor expression of GPX4 and high expression of COX-2 were witnessed in cerebral I/R injury models. MSCs-EVs/Fer-1 exerted its protective effects against cerebral I/R injury by upregulating GPX4 expression and inhibiting COX-2 expression. Taken together, our study indicates that MSCs-EVs/Fer-1 may be an attractive therapeutic target for the treatment of cerebral I/R injury due to its anti-ferroptotic properties.

Ferrostatin-1（Fer-1，ferroptosis 抑制剂）在脑缺血中的关键作用的越来越多的证据促使我们探索通过骨髓间充质干细胞衍生的细胞外囊泡（MSCs-EVs）传递 Fer-1 的分子机制作用在脑缺血再灌注 (I/R) 损伤中。开发了小鼠体内大脑中动脉闭塞 (MCAO) 和海马神经元体外氧-葡萄糖剥夺/再灌注 (OGD/R) 来模拟大脑 I/R 损伤。在确认 Fer-1 被 MSCs-EV 成功递送至神经元后，我们发现装载 Fer-1 (MSCs-EVs/Fer-1) 的 MSCs-EV 减少了神经元凋亡并增强了活力，同时减少了炎症和铁死亡. Fer-1 对 GPX4/COX2 轴的调节通过生物信息学研究预测，并通过功能实验验证。体内实验进一步证实，MSCs-EVs/Fer-1 可改善小鼠脑 I/R 损伤。此外，在脑 I/R 损伤模型中观察到 GPX4 的低表达和 COX-2 的高表达。MSCs-EVs/Fer-1通过上调GPX4表达和抑制COX-2表达发挥其对脑I/R损伤的保护作用。综上所述，我们的研究表明，由于 MSCs-EVs/Fer-1 的抗铁死亡特性，它可能是治疗脑 I/R 损伤的一个有吸引力的治疗靶点。在脑 I/R 损伤模型中观察到 GPX4 的低表达和 COX-2 的高表达。MSCs-EVs/Fer-1通过上调GPX4表达和抑制COX-2表达发挥其对脑I/R损伤的保护作用。综上所述，我们的研究表明，由于 MSCs-EVs/Fer-1 的抗铁死亡特性，它可能是治疗脑 I/R 损伤的一个有吸引力的治疗靶点。在脑 I/R 损伤模型中观察到 GPX4 的低表达和 COX-2 的高表达。MSCs-EVs/Fer-1通过上调GPX4表达和抑制COX-2表达发挥其对脑I/R损伤的保护作用。综上所述，我们的研究表明，由于 MSCs-EVs/Fer-1 的抗铁死亡特性，它可能是治疗脑 I/R 损伤的一个有吸引力的治疗靶点。