CircGRB10 Mitigates Ischemic Neuronal Injuries through Ferroptosis Regulation via miR-6838-5p/FBXW7 Axis

Abstract

Circular RNAs (circRNAs) exhibit widespread expression within the brain and are pivotal in the development of numerous central nervous system disorders, particularly in neuronal damage associated with ischemic stroke. Our research focuses on mmu_circ_0009119 (circGRB10) and its pivotal role in this process. Through studies on healthy controls and ischemic stroke patients, along with in vitro simulations using the oxygen and glucose deprivation/reoxygenation (OGD/R) model in HT22 neuronal cells, we revealed a significant upregulation of circGRB10 in a mouse model of ischemic stroke. Deficiency in circGRB10 restored cell viability in OGD/R-induced HT22 cells by upregulating FBXW7 through sequestering miR-6838-5p. Inhibition of miR-6838-3p weakened the impact of circGRB10 silencing on cell survival and Ferroptosis in OGD/R-induced HT22 cells. Additionally, the upregulation of FBXW7 counteracted the effect of miR-6838-5p upregulation on OGD/R-induced HT22 cells. On another note, circGRB10 suppressed cell survival and accelerated Ferroptosis in OGD/R-induced HT22 cells by sequestering miR-6838-5p to upregulate the FBXW7 axis. This study elucidates the mechanism by which circGRB10, through the circGRB10/miR-6838-5p/FBXW7 axis, regulates neuronal survival after ischemic stroke, providing crucial insights into its potential as a therapeutic target for ischemic stroke.