中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 2893-2903.doi: 10.4103/NRR.NRR-D-25-00030

• 原著:脑损伤修复保护与再生 • 上一篇    

双微体同源基因2-谷胱甘肽过氧化物酶4-铁死亡调控轴具有神经毒性作用

  

  • 出版日期:2026-07-15 发布日期:2025-10-21

MDM2–GPX4–ferroptosis regulatory axis exerts neurotoxic effects in intracerebral hemorrhage

Yunhu Yu1, #, Tao Liu2, #, Yunpeng Cai3 , Yuanmei Song4 , Hang Zhou4 , Fang Cao5, *, Rongcai Jiang1, 2, *   

  1. 1 Department of Neurosurgery, Tianjin Neurological Institute, State Key Laboratory of Experimental Hematology, Laboratory of Post‐Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin, China;  2 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China;  3 Department of Neurosurgery, South China Hospital of Shenzhen University, Shenzhen, Guangdong Province, China;  4 Department of Neurosurgery, the People’s Hospital of HongHuaGang District of ZunYi, Zunyi, Guizhou Province, China;  5 Department of Neurosurgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
  • Online:2026-07-15 Published:2025-10-21
  • Contact: Rongcai Jiang, MD, PhD, jiangrongcai@tmu.edu.cn; Fang Cao, MD, PhD, caof@zmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82311530117 (to RJ) and 82260260 (to FC).

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摘要：

铁死亡在脑出血的神经损伤中起着关键作用，并与鼠双微体同源基因2的上调有关。研究与鼠双微体同源基因2相关的铁蛋白沉积的机制可以发现治疗脑出血的新疗法。实验通过对 BV2 小胶质细胞进行氧糖剥夺联合血红素处理建立了脑出血体外模型。通过 RNA 干扰转导和慢病毒过表达研究了鼠双微体同源基因2在调控铁死亡中的作用。此外，还构建了使用和不使用鼠双微体同源基因2抑制剂brigimadlin的脑出血小鼠模型。结果发现，鼠双微体同源基因2失调与氧糖剥夺结合血红素诱导的BV2小胶质细胞铁死亡和M1/M2极化有关。鼠双微体同源基因2诱导谷胱甘肽过氧化物酶4泛素化和降解，从而调节BV2小胶质细胞的铁死亡和炎症反应。WTAP可诱导鼠双微体同源基因2 N6-甲基腺苷修饰，并调节铁氧化和炎症反应。体内分析表明，brigimadlin能改善脑出血小鼠的神经功能缺损和空间记忆。总之，WTAP调节鼠双微体同源基因2 N6-甲基腺苷修饰，鼠双微体同源基因2诱导谷胱甘肽过氧化物酶4泛素化和降解。这种调控促进了脑出血的小胶质细胞铁死亡和炎症反应，表明鼠双微体同源基因2-谷胱甘肽过氧化物酶4-铁死亡调控轴具有神经毒性作用。这些发现为治疗脑出血相关脑损伤找到了潜在的基因治疗靶点谷胱甘肽过氧化物酶4。

https://orcid.org/0000-0002-9119-0115 (Rongcai Jiang); https://orcid.org/0000-0002-4900-8957 (Fang Cao)

关键词: 脑出血, 鼠双微体同源基因2, 谷胱甘肽过氧化物酶4, 泛素化, N6-甲基腺苷, 铁死亡

Abstract: Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2. Investigating the mechanism underlying murine double minute 2-related ferroptosis could help identify new therapies for intracerebral hemorrhage. An in vitro intracerebral hemorrhage model was established by treating BV2 microglial cells with oxygen–glucose deprivation combined with hemin. The role of murine double minute 2 in regulating ferroptosis was investigated via transduction with RNA interference and lentivirus overexpression. Furthermore, intracerebral hemorrhage mouse models were constructed with and without an murine double minute 2 inhibitor (brigimadlin), and behavioral assays were performed to assess the learning ability and cognitive function. Murine double minute 2 dysregulation was associated with oxygen–glucose deprivation combined with hemin-induced BV2 microglial cell ferroptosis and M1/M2 polarization. The results suggested that murine double minute 2 induced glutathione peroxidase 4 ubiquitination and degradation to regulate ferroptosis and inflammatory responses in BV2 microglial cells. Mechanistically, Wilms tumor 1-associated protein induced murine double minute 2 N6-methyladenosine (m6A) modification and regulated ferroptosis and inflammatory responses. In vivo analysis showed that brigimadlin improved neurological deficits and spatial memory in mice with intracerebral hemorrhage. In summary, the results indicate that Wilms tumor 1-associated protein regulates murine double minute 2 m6A modification, and murine double minute 2 induces glutathione peroxidase 4 ubiquitination and degradation. This regulation promotes ferroptosis and inflammatory responses in oxygen–glucose deprivation combined with hemin-induced BV2 microglial cells, suggesting that the murine double minute 2–glutathione peroxidase 4–ferroptosis regulatory axis exerts neurotoxic effects. These findings identify glutathione peroxidase 4 as a potential gene therapy target for intracerebral hemorrhage–related brain injury.

Key words: ferroptosis, glutathione peroxidase 4, intracerebral hemorrhage, m6A, murine double minute 2, ubiquitination