Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (7): 2893-2903.doi: 10.4103/NRR.NRR-D-25-00030

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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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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