HIF3A-mediated aberrant activation of TXNIP promotes Alzheimer's disease progression

Oxidative stress (OS) is a hallmark of Alzheimer's disease (AD), yet the cell type-specific mechanisms remain unclear. We analyzed a single-cell RNA sequencing (scRNA-seq) dataset to assess OS-related features in AD. OS scores were calculated using multiple algorithms, and differential expression, enrichment, protein-protein interaction (PPI) network, and machine learning (ML) approaches were applied to identify key genes. Validation was performed at both bulk and single-cell levels, and functional assays were conducted to elucidate molecular mechanisms. OS activity was significantly elevated in AD, with pronounced heterogeneity across cell types. Astrocytes exhibited the highest OS activity, and their proportion was markedly reduced in AD. We identified 54 OS-upregulated genes enriched in neurodevelopment and synaptic processes. Through integrative ML, HIF3A was pinpointed as a key OS-related gene, showing high expression in astrocytes and strong correlation with OS pathways. Mechanistically, HIF3A directly bound to the TXNIP promoter, upregulated TXNIP expression, and thereby enhanced mitochondrial ROS production, impaired energy metabolism, and exacerbated OS in astrocytes. Our findings reveal that astrocytic HIF3A mediates aberrant OS responses in AD via transcriptional upregulation of TXNIP, offering insights into potential therapeutic targets to mitigate oxidative damage in AD.