PEBP1 inhibition as a therapeutic target for neurological recovery in ischemic stroke

Ischemic stroke poses a substantial clinical and socioeconomic burden due to limited therapeutic efficacy and poor neurological outcomes. To uncover novel gene targets for intervention, we conducted an integrative analysis combining single-cell RNA sequencing with Mendelian randomization using large-scale genomic datasets from the European Bioinformatics Institute (34,593 cases and 624,214 controls), with validation in an independent European Bioinformatics Institute dataset (86,668 cases and 1,503,898 controls) and the UK Biobank (26,052 cases and 487,214 controls). Colocalization analysis identified four core genes-PEBP1, BMP4, APOA1 and CD86-strongly associated with ischemic stroke risk, with a posterior probability of a shared causal variant greater than 0.8. Among them, PEBP1 was markedly upregulated post-ischemia, particularly in endothelial cells, as confirmed by quantitative PCR and immunofluorescence in a middle cerebral artery occlusion model. Both pharmacological inhibition of PEBP1 with FerroLOXIN-1 and AAV-BI30-mediated shRNA knockdown reduced cerebral infarct volume, enhanced neuronal survival, and improved neurological functional recovery. In vitro, FerroLOXIN-1 enhanced cell proliferation and viability under oxygen-glucose deprivation conditions, with potential off-target effects of the interventions validated. Mechanistically, these effects were mediated through activation of the Akt/p38 MAPK signaling cascade. These findings highlight PEBP1 as a central mediator of ischemia-induced neuronal injury and a potential therapeutic target. The convergence of transcriptomic, genetic and experimental validation supports the translational relevance of PEBP1 inhibition in post-stroke neuroregeneration.