Xu Zhongmou, Li Haiying, Li Xiang, Lu Jinxin, Cao Chang, Peng Lu, Li Lianxin, Zhang John, Chen Gang
Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
Institute of Stroke Research, Soochow University, Suzhou, 215006, China.
Neurosci Bull. 2025 Feb 14. doi: 10.1007/s12264-025-01355-x.
During the hyperacute phase of intracerebral hemorrhage (ICH), the mass effect and blood components mechanically lead to brain damage and neurotoxicity. Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake, culminating in ferroptosis in neurons. M6A (N6-methyladenosine) modification, the most prevalent mRNA modification, plays a critical role in various cell death pathways. The Fto (fat mass and obesity-associated protein) demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels. Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis. Applying nanopore direct RNA sequencing, we identified voltage-dependent anion channel 3 (Vdac3) as a potential target associated with ferroptosis. Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA. These findings elucidate the intricate interplay between Fto, Vdac3, m6A methylation, and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
在脑出血（ICH）的超急性期，占位效应和血液成分会机械性地导致脑损伤和神经毒性。我们的研究结果表明，占位效应和转铁蛋白会引发神经元氧化应激和铁摄取，最终导致神经元发生铁死亡。m6A（N6-甲基腺苷）修饰是最普遍的mRNA修饰，在各种细胞死亡途径中起关键作用。Fto（脂肪量和肥胖相关蛋白）去甲基化酶通过调节m6A mRNA水平参与了多种神经疾病的信号通路。调节神经元中的Fto蛋白水平可有效减轻占位效应诱导的神经元铁死亡。通过应用纳米孔直接RNA测序，我们确定电压依赖性阴离子通道3（Vdac3）是与铁死亡相关的潜在靶点。Fto通过调节Vdac3 mRNA的m6A甲基化影响神经元铁死亡。这些发现阐明了脑出血超急性期神经元中Fto、Vdac3、m6A甲基化和铁死亡之间的复杂相互作用，并为脑出血提出了新的治疗策略。
