Zhao Xiaoyong, Zhang Xiaoli, Wu Liangzhi, Liu Xiaohe, Pan Yongquan, Lv Taiquan, Xu Mingyang, Yang Kongbin, Wang Xiangyu
Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China; Department of Neurosurgery, The Fifth Hospital of Guangzhou Medical University, Guangzhou 510632, China.
Department of Obstetrics and Gynecology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510632, China.
Neurobiol Dis. 2025 Apr;207:106811. doi: 10.1016/j.nbd.2025.106811. Epub 2025 Jan 22.
Central nervous system (CNS) repair after injury is a challenging process limited by inflammation and neuronal apoptosis. This study identifies Wilms' tumor 1-associating protein (WTAP) as a pivotal regulator of neuronal protection and repair through m6A methylation of STAT3 mRNA. By employing spinal cord injury (SCI) as a representative model of CNS injury, transcriptomic analyses reveal WTAP as a key mediator of pathways related to neuronal autophagy and inflammation regulation. WTAP enhances neuronal autophagy by suppressing STAT3 expression and activity, which inhibits the NLRP3 inflammatory pathway. Functional studies demonstrate that WTAP knockdown exacerbates neuronal apoptosis, whereas overexpression improves cell viability, autophagy, and motor recovery. In vivo, WTAP promotes SCI repair via m6A-mediated suppression of STAT3 and regulation of the NLRP3 signaling pathway, highlighting its therapeutic potential for CNS injury repair.
损伤后中枢神经系统（CNS）的修复是一个具有挑战性的过程，受到炎症和神经元凋亡的限制。本研究确定了威尔姆斯瘤1相关蛋白（WTAP）是通过STAT3 mRNA的m6A甲基化对神经元起到保护和修复作用的关键调节因子。通过将脊髓损伤（SCI）作为中枢神经系统损伤的代表性模型，转录组分析显示WTAP是与神经元自噬和炎症调节相关通路的关键介质。WTAP通过抑制STAT3的表达和活性来增强神经元自噬，从而抑制NLRP3炎症通路。功能研究表明，敲低WTAP会加剧神经元凋亡，而过表达则会提高细胞活力、自噬水平并促进运动功能恢复。在体内，WTAP通过m6A介导的对STAT3的抑制和对NLRP3信号通路的调节来促进脊髓损伤的修复，突出了其在中枢神经系统损伤修复中的治疗潜力。
