NRF2 binding in HMC3 human microglia

Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative NRF2 directly target genes involved in inflammation (e.g., IL6, CDK6) and another five in autophagy (e.g., TFE3, SQSTM1). Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Our findings revealed new direct NRF2 target genes, highlighting dual role of NRF2 in suppressing inflammation and enhancing autophagy, thus providing novel insights for therapeutic interventions in AD.