Wu Liaozhang, Luo Zunwei, Luo Fuli, Huang Tingting, Cen Yifang, Rao Guosheng, Zhao Zhijie, Ou Renyang, Zhou Manhong
Dalian Medical University, Dalian City, Liaoning Province, P.R. China.
Department of Emergency, The Affiliated Hospital of Zunyi Medical University, Zunyi City, Guizhou Province, P.R. China.
Free Radic Res. 2025 Mar;59(3):274-288. doi: 10.1080/10715762.2025.2482774. Epub 2025 Mar 28.
The biological effects of edaravone (Eda), a free radical scavenger, include anti-inflammatory, antioxidant, and neuroprotective qualities. Nevertheless, the function and potential mechanisms of Eda in central nervous system injury damage are still unknown. A rat model of acute diquat toxicity was constructed to observe the pathological changes in brain tissues after diquat administration. The changes of mitophagy and ferroptosis in PC12 cells were assessed to the protective activity of Eda. To assess the methylation levels of m6A RNA, the EpiQuik m6A RNA Methylation Quantification Kit was utilized. RIP, dual luciferase reporter assay and mRNA stability detection confirm the relationship between METTL14 and Aldh11l1. Knockdown and overexpression experiments were performed to determine the effects of METTL14 and Aldh1l1 on rats and PC12 cells stimulated with diquat under Eda treatment. Eda dramatically ameliorated diquat-induced central nervous system injury. Eda notably attenuated apoptosis, pro-inflammatory cytokines activation, and oxidative stress damage in diquat-induced rats. Eda significantly suppressed apoptosis, mitophagy and ferroptosis after diquat-stimulated PC12 cells. Mitophagy inhibitor Mdivi-1 reversed the induction of ferroptosis effects of diquat via decreased Fe2+ content and increased Ca2+ level. knockdown of METTL14 reversed the therapeutic effect of Eda on diquat-induced injury. Eda promoted METTL14-mediated Aldh1l1 m6A methylation and alleviates acute central nervous system injury induced by diquat in vivo and in vitro. Eda has a protective effect on diquat-induced nervous system injury, and its mechanism may be related to the activation of m6A modification of Aldh11l1 by METTL14 and the inhibition of mitophagy and. ferroptosis.
依达拉奉（Eda）作为一种自由基清除剂，其生物学效应包括抗炎、抗氧化和神经保护特性。然而，Eda在中枢神经系统损伤中的作用及潜在机制仍不清楚。构建急性百草枯中毒大鼠模型，观察百草枯给药后脑组织的病理变化。评估PC12细胞中线粒体自噬和铁死亡的变化，以研究Eda的保护活性。使用EpiQuik m6A RNA甲基化定量试剂盒评估m6A RNA的甲基化水平。通过RNA免疫沉淀、双荧光素酶报告基因检测和mRNA稳定性检测来证实METTL14与Aldh11l1之间的关系。进行敲低和过表达实验，以确定METTL14和Aldh1l1对Eda处理下百草枯刺激的大鼠和PC12细胞的影响。Eda显著改善了百草枯诱导的中枢神经系统损伤。Eda明显减轻了百草枯诱导的大鼠的细胞凋亡、促炎细胞因子激活和氧化应激损伤。Eda显著抑制了百草枯刺激后的PC12细胞的凋亡、线粒体自噬和铁死亡。线粒体自噬抑制剂Mdivi-1通过降低Fe2+含量和增加Ca2+水平，逆转了百草枯诱导的铁死亡效应。敲低METTL14可逆转Eda对百草枯诱导损伤的治疗效果。Eda促进METTL14介导的Aldh1l1 m6A甲基化，并在体内和体外减轻百草枯诱导的急性中枢神经系统损伤。Eda对百草枯诱导的神经系统损伤具有保护作用，其机制可能与METTL14激活Aldh11l1的m6A修饰以及抑制线粒体自噬和铁死亡有关。
