Peng Qiang, Deng Yang, Xu Zhaohan, Duan Rui, Wang Wei, Wang Shiyao, Hong Ye, Wang Qingguang, Zhang Yingdong
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210006, Jiangsu, China.
Biochem Pharmacol. 2024 Dec;230(Pt 2):116603. doi: 10.1016/j.bcp.2024.116603. Epub 2024 Oct 30.
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.
脂肪量与肥胖相关蛋白（FTO）是一种去甲基化酶，最近被发现对急性缺血性中风（AIS）具有保护作用，但其潜在机制在很大程度上尚不清楚。新研究发现，某些微小RNA（miRNA）的表达可能受N6-甲基腺苷（m6A）水平的影响。在此，我们通过高通量测序和定量聚合酶链反应发现，miR-320-3p在AIS患者中显著上调。miR-320-3p加重了大脑中动脉闭塞/再灌注模型小鼠的神经行为表现、梗死体积和组织病理学变化。机制上，miR-320-3p与溶质载体家族7成员11（SLC7A11）mRNA的3'非翻译区结合，促进神经元氧糖剥夺/复氧诱导的氧化应激和铁死亡。FTO抑制初级转录本pri-miR-320的m6A甲基化以及miR-320-3p的成熟，从而对AIS后的脑缺血/再灌注损伤具有保护作用。临床上，我们还证实了AIS患者外周血中FTO和SLC7A11 mRNA的下调及其与miR-320-3p表达的相关性。我们的研究发现，FTO以m6A依赖的方式通过miR-320-3p/SLC7A11轴抑制铁死亡，从而对脑缺血再灌注损伤具有保护作用。我们的结果为AIS后脑缺血/再灌注损伤提供了一个有前景的治疗靶点。
