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

作者：Yun-hu Yu, Tao Liu, Yunpeng Cai, Yuanmei Song, Hang Zhou, Fang Cao, Rongcai Jiang · 发表于：Neural Regeneration Research · 年份：2025 · DOI：10.4103/nrr.nrr-d-25-00030 · 被引用次数：3 · 研究领域：Cancer-related gene regulation、Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research

Export 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 i...