METTL14 Promotes Ischemic Stroke-induced Brain Injury by Stabilizing HDAC3 Expression in an m6A-IGF2BP3 Mechanism

Area of Science:

• Neuroscience
• Molecular Biology
• Epigenetics

Background:

• N6-methyladenosine (m6A) modification is crucial in ischemic stroke (IS).
• The role of Methyltransferase-like 14 (METTL14) in IS remains unclear.
• Investigating METTL14's function and mechanism in cerebral IS is essential.

Purpose of the Study:

• To investigate the function and mechanism of METTL14 in cerebral ischemic stroke.
• To explore METTL14's role in microglial activation and brain injury.
• To elucidate the molecular pathways regulated by METTL14 in IS.

Main Methods:

• Established in vitro (murine BV-2 microglial cell OGD/R) and in vivo (rat MCAO) models of ischemic stroke.
• Assessed METTL14, Histone Deacetylase 3 (HDAC3), and cGAS-STING pathway proteins via qRT-PCR and western blotting.
• Evaluated cell proliferation, inflammation, microglia polarization, pyroptosis, m6A modification, infarct volume, and neurological scores.

Main Results:

• METTL14 levels were elevated in ischemic conditions and brain tissues.
• METTL14 silencing inhibited microglial proliferation, inflammation, and pyroptosis, and ameliorated brain injury.
• METTL14 promoted HDAC3 m6A modification in an IGF2BP3-dependent manner, activating the cGAS-STING pathway.

Conclusions:

• METTL14 exacerbates ischemic stroke by inducing HDAC3 m6A modification and activating the cGAS-STING pathway.
• METTL14 silencing exhibits neuroprotective effects, offering a potential therapeutic strategy for IS.
• This study provides novel insights into the epigenetic regulation of cerebral ischemic stroke.