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

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Ferroptosis is implicated in nerve injury following intracerebral hemorrhage (ICH).
• Murine double minute 2 (MDM2) is upregulated in ICH and linked to ferroptosis.
• Understanding MDM2's role in ferroptosis could reveal novel ICH therapies.

Purpose of the Study:

• To investigate the mechanism of MDM2-regulated ferroptosis in the context of ICH.
• To explore the therapeutic potential of targeting the MDM2-ferroptosis pathway.

Main Methods:

• Established an in vitro ICH model using BV2 microglial cells subjected to oxygen-glucose deprivation and hemin.
• Utilized RNA interference and lentivirus overexpression to manipulate MDM2 levels.
• Administered an MDM2 inhibitor (brigimadlin) to ICH mouse models.
• Assessed neurological deficits and cognitive function through behavioral assays.

Main Results:

• MDM2 dysregulation promoted ferroptosis and M1/M2 polarization in microglial cells.
• MDM2 induced glutathione peroxidase 4 (GPX4) ubiquitination and degradation, regulating ferroptosis and inflammation.
• Wilms tumor 1-associated protein (WTAP) mediated MDM2 N6-methyladenosine (m6A) modification, influencing ferroptosis and inflammation.
• Brigimadlin treatment improved neurological function and spatial memory in ICH mice.

Conclusions:

• WTAP regulates MDM2 m6A modification, which in turn drives GPX4 ubiquitination and degradation.
• The MDM2-GPX4-ferroptosis axis promotes neurotoxicity in ICH.
• GPX4 emerges as a potential gene therapy target for ICH-induced brain injury.