Wang_2026_Neurochem.Res_51_

This study elucidates the role of microglia in ferroptosis and neuroinflammation following ischemic stroke and defines the underlying molecular mechanisms. Single-cell transcriptomic analysis revealed that multiple brain cell types in the MCAO mouse model exhibited ferroptosis-related signatures, with microglia showing the most pronounced changes. Differentially expressed genes in post-stroke microglia were significantly enriched in ferroptosis-associated pathways. Further investigations demonstrated that both in vivo (tMCAO/R) and in vitro (OGD/R-treated microglia) models exhibited marked upregulation of the transcription factor Tbp and the lipid metabolism enzyme Lpl, accompanied by increased expression of pro-inflammatory chemokines CCL2, CCL3, and CCL4. Ultrastructural, biochemical, and molecular analyses confirmed canonical features of ferroptosis, including mitochondrial damage, elevated lipid peroxidation, increased ACSL4 and NCOA4 levels, and reduced GPX4 expression. Mechanistically, Tbp directly bound to and transcriptionally activated the Lpl promoter. Activation of the Tbp-Lpl axis by OGD/R promoted pro-inflammatory polarization and chemokine release in microglia and was associated with exacerbated ferroptotic injury, whereas Tbp knockdown effectively reversed these effects. Collectively, these findings demonstrate that ischemic stroke activates the Tbp-Lpl transcriptional regulatory axis in microglia, coordinately driving lipid metabolic reprogramming, amplifying inflammation, and promoting ferroptosis. This study provides new mechanistic insights into post-stroke neuronal injury and identifies Tbp as a potential therapeutic target for modulating microglial ferroptosis and neuroinflammation.