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NRF2 activation by CDDO-Im regulates inflammatory and autophagy pathways in human microglial cells

Ching-Tung Chu1, Akira Uruno1, Takafumi Suzuki2

  • 1Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.

Free Radical Biology & Medicine
|November 22, 2025
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) activation in microglia reduces Alzheimer

Area of Science:

  • Neuroscience
  • Immunology
  • Molecular Biology

Background:

  • Alzheimer's disease (AD) pathology involves amyloid-beta plaques, neurofibrillary tangles, oxidative stress, and neuroinflammation.
  • Microglia, brain's immune cells, are crucial for clearing pathological aggregates and damaged neurons.
  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular defense against oxidative stress, showing therapeutic potential in AD models.

Purpose of the Study:

  • To identify direct microglial targets of Nuclear factor erythroid 2-related factor 2 (NRF2).
  • To investigate the role of NRF2 activation in modulating microglial inflammation and autophagy.
  • To explore NRF2-mediated pathways as potential therapeutic targets for Alzheimer's disease.

Main Methods:

  • Utilized human microglial cells (HMC3) stimulated with Interferon-gamma (IFN-γ) or amyloid-beta (Aβ).
  • Activated NRF2 using CDDO-Im and analyzed gene expression via RNA-sequencing and NRF2 binding sites using ChIP-sequencing.
  • Assessed autophagy markers (LC3-II/LC3-I ratio) and analyzed public single-cell transcriptomic data from AD brains.

Main Results:

  • NRF2 activation significantly suppressed inflammation in HMC3 cells.
  • Identified direct NRF2 target genes involved in both inflammation (e.g., IL6, CDK6) and autophagy (e.g., TFE3, SQSTM1).
  • CDDO-Im treatment enhanced autophagy, and NRF2's role in autophagy regulation within AD microglia was confirmed.

Conclusions:

  • Revealed novel direct NRF2 target genes in microglia relevant to Alzheimer's disease.
  • Demonstrated NRF2's dual function in suppressing neuroinflammation and promoting autophagy.
  • These findings offer new therapeutic strategies targeting NRF2 pathways for Alzheimer's disease treatment.
Keywords:
Alzheimer's disease (AD)Amyloid beta (Aβ)Interferon-gamma (IFN-γ)MicrogliaNRF2 activation

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