2026年7月2日，同济大学梅馨予小组在《神经科学通报》杂志发表论文，宣布他们的研究认为Cofilin-1的N-同型半胱氨酸化通过破坏肌动蛋白动力学加重癫痫病理生理。

该研究团队发现N-同型半胱氨酸化Cofilin-1 （N-Hcy-CFL1）是Hcy水平升高与儿童癫痫之间的分子联系。该研究组在癫痫患者和高同型半胱氨酸血症的同母位模型中检测到N-Hcy-CFL1。质谱分析鉴定了CFL1中hcy依赖的赖氨酸修饰，功能分析，包括肌动蛋白解聚、F/G-肌动蛋白比率和轴突伸长，表明CFL1活性受损，随之而来的是细胞骨架刚性。这些变化表现为F-肌动蛋白水平升高，F/G-肌动蛋白比值升高，轴突生长异常。

在体内，高同型半胱氨酸血症小鼠表现出长时间的癫痫发作和轴突重塑，这两种症状都被CFL1定向干预所减轻。临床上，血液Hcy水平与患者脑组织中N-Hcy-CFL1水平相关，支持其作为生物标志物的潜力。总之，这些发现确定了N-Hcy-CFL1是一种致病介质，并表明N-同型半胱氨酸化是一种超越传统Hcy降低策略的治疗靶点。

研究人员表示，升高的同型半胱氨酸（Hcy）水平有助于儿童癫痫的发生和发展。然而，降低Hcy治疗提供有限的益处，提示其他致病机制。

附：英文原文

Title: N-Homocysteinylation of Cofilin-1 Aggravates Epileptic Pathophysiology via Disruption of Actin Dynamics

Author: Mei, Xinyu, Liu, Yi, Fang, Chuantao, Guo, Jingjing, Tan, Yanfeng, Shi, Ying, Xiao, Jianbo, Qi, Dashi

Issue&Volume: 2026-07-02

Abstract: Elevated homocysteine (Hcy) levels contribute to the onset and progression of childhood epilepsy. However, Hcy-lowering therapies provide limited benefits, suggesting additional pathogenic mechanisms. Here, we identified N-homocysteinylated Cofilin-1 (N-Hcy-CFL1) as a molecular link between elevated Hcy levels and childhood epilepsy. We detected N-Hcy-CFL1 in patients with epilepsy and in a mouse model of hyperhomocysteinemia. Mass spectrometry identified Hcy-dependent lysine modifications in CFL1, and functional assays, including actin depolymerization, the F/G-actin ratio, and axonal elongation, demonstrated impaired CFL1 activity and consequent cytoskeletal rigidity. These changes manifested as increased F-actin levels, increased F/G-actin ratio, and abnormal axonal growth. In vivo, hyperhomocysteinemic mice exhibited prolonged seizures and axonal remodeling, both of which were attenuated by CFL1-directed interventions. Clinically, blood Hcy levels correlated with N-Hcy-CFL1 levels in patients’ brain tissues, supporting its potential as a biomarker. Together, these findings identify N-Hcy-CFL1 as a pathogenic mediator and suggest that N-homocysteinylation is a therapeutic target beyond conventional Hcy-lowering strategies.

DOI: 10.1007/s12264-026-01652-z

Source: https://link.springer.com/article/10.1007/s12264-026-01652-z