Anti-Ferroptotic Effects of bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Loaded with Ferrostatin-1 in Cerebral ischemia-reperfusion Injury Associate with the GPX4/COX-2 Axis.

Abstract

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.