Fat mass and obesity-associated protein alleviates cerebral ischemia/reperfusion injury by inhibiting ferroptosis via miR-320-3p/SLC7A11 axis

Abstract

Fat mass and obesity-associated protein (FTO) is a demethylase and has recently been found to have a protective effect in acute ischemic stroke (AIS), but the underlying mechanism is unclear to a large extent. New studies have found that the expression of certain miRNAs may be affected by N6-methyladenosine (m6A) levels. Here, using high-throughput sequencing and quantitative polymerase chain reaction, we found miR-320-3p was significantly up-regulated in AIS patients. miR-320-3p aggravated the neurobehavioral manifestation, infarct volume and histopathology of middle cerebral artery occlusion/reperfusion model mice. Mechanically, miR-320-3p binds to the 3′ untranslated region of solute carrier family 7 member 11 (SLC7A11) mRNA, promoting oxidative stress and ferroptosis induced by oxygen-glucose deprivation/reoxygenation in neurons. FTO inhibited the m6A methylation of the primary transcript pri-miR-320 and the maturation of miR-320-3p, thus having a protective effect on cerebral ischemia/reperfusion injury after AIS. Clinically, we also confirmed the down-regulation of FTO and SLC7A11 mRNA in the peripheral blood of AIS patients and their correlation with the expression of miR-320-3p. Our study found that FTO inhibits ferroptosis through miR-320-3p/SLC7A11 axis in an m6A-dependent manner, and thus has a protective effect on cerebral ischemic reperfusion injury. Our results provided a promising therapeutic target of cerebral ischemia/reperfusion injury after AIS.