FTO/miR-503-5p/USP10 axis regulates neuronal endoplasmic reticulum stress-mediated apoptosis in ischemic stroke

MiR-503-5p is reported to be implicated in ischemic diseases, including those affecting the heart and brain; however, its specific functions and upstream regulatory mechanisms in acute ischemic stroke (AIS) remain a mystery. To address this, we employed the middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models to simulate ischemic/reperfusion conditions in vivo and in vitro. MiR-503-5p was found to exacerbate the brain infarct volume, neuronal damage and neurobehavioral impairment in the MCAO/R mice. In primary neurons, miR-503-5p directly targeted and downregulated ubiquitin-specific protease 10 (USP10), which was reported to be an anti-apoptotic factor. MiR-503-5p significantly elevated the endoplasmic reticulum stress (ERS) biomarkers glucose-regulated protein 78 (GRP78) and the C/EBP homologous protein (CHOP), and exacerbated apoptosis in OGD/R primary neurons, while overexpression of USP10 partially reversed this change. Further investigations indicated that the maturation process of miR-503-5p in neurons was inhibited by demethylase fat mass and obesity-associated protein (FTO) in an m6A-dependent manner. Rescue experiments in vitro and in vivo demonstrated that FTO inhibited ERS-mediated apoptosis by regulating miR-503-5p/USP10 axis. These findings underscore the therapeutic potential of miR-503-5p/USP10 axis and illuminate the neuroprotective effects of FTO on AIS.