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METTL14/m6A/CEBPD axis: A critical player in chronic cerebral hypoperfusion-associated neuroinflammation

Huanhuan Wang1, Hanshu Zhao1, Jiadi Gao1

  • 1Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China.

Free Radical Biology & Medicine
|March 6, 2026
PubMed

Insights

Targeting METTL14 reduces neuroinflammation and cognitive decline in vascular dementia. This epigenetic approach suppresses microglial M1 polarization by stabilizing CEBPD mRNA, offering a potential therapy for this condition.

Area of Science:

  • Neuroscience
  • Epigenetics
  • Molecular Biology

Background:

  • Vascular dementia (VaD) involves cognitive decline due to chronic cerebral hypoperfusion (CCH) and neuroinflammation.
  • Microglial M1 polarization is a key driver of CCH-related neuroinflammation, but its epigenetic regulation is not fully understood.
  • N6-methyladenosine (m6A) modification, particularly involving METTL14, and CCAAT enhancer binding protein delta (CEBPD) are implicated in brain inflammation.

Purpose of the Study:

  • To investigate the role of METTL14 in microglial polarization and its impact on chronic cerebral hypoperfusion (CCH) pathology.
  • To elucidate the epigenetic mechanism by which METTL14 influences neuroinflammation and cognitive function in vascular dementia (VaD).

Main Methods:

  • In vitro studies using HMC3 cells treated with LPS/TNF-α to assess METTL14 and CEBPD expression and microglial polarization.
  • In vivo studies using bilateral common carotid artery occlusion (BCCAo)-induced CCH rat models.
  • Short hairpin RNA (shRNA) and adeno-associated virus (AAV) mediated knockdown of METTL14.
  • RNA immunoprecipitation-PCR (RIP-PCR) and m6A-specific immunoprecipitation-PCR (MeRIP-qPCR) to confirm m6A modification and mRNA stability.
  • Assessment of cognitive function using spatial learning and memory and object recognition tests.

Main Results:

  • METTL14 knockdown suppressed LPS/TNF-α-induced M1 polarization in HMC3 cells, reducing pro-inflammatory factors and NF-κB activation.
  • In CCH rats, hippocampal METTL14 and CEBPD levels were elevated.
  • AAV-mediated METTL14 knockdown in CCH rats attenuated neuroinflammation, neuronal apoptosis, and improved cognitive deficits.
  • METTL14 was confirmed to enhance CEBPD mRNA stability through m6A modification, with CEBPD acting as a downstream mediator.

Conclusions:

  • METTL14 knockdown inhibits microglial M1 polarization and neuroinflammation in CCH by impairing CEBPD mRNA stability via m6A modification.
  • This process involves the TLR4/MyD88/NF-κB pathway, leading to alleviation of cognitive impairment in vascular dementia.
  • METTL14 represents a potential epigenetic therapeutic target for vascular dementia.
Keywords:
CCAAT enhancer binding protein deltaChronic cerebral hypoperfusionMethyltransferase-like 14Microglial polarizationm6A modification

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