Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Ferroptosis is closely involved in the pathological process of traumatic brain injury (TBI), and Puerarin has potential neuroprotective activity. Objectives: This study aims to investigate the main targets and underlying mechanisms of Puerarin against traumatic brain injury (TBI) from the perspective of ferroptosis. Methods: The GSE104687 dataset (194 TBI and 182 control samples) was obtained from Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) were identified using the R package limma. The ferroptosis-related genes (FRGs) were compiled from GeneCards and MSigDB and Puerarin-related targets were retrieved from PubChem, Similarity Ensemble Approach (SEA) and SwissTargetPrediction. Four key ferroptosis-related DEGs (FDTRDEGs) were obtained by intersecting DEGs with FRGs and Puerarin targets: NQO1, VCP, PML and RELA. Finally, a mouse TBI model was established to evaluate Puerarin’s effects on brain injury, neurological deficits, brain water content and molecular changes across sham, TBI and TBI + Puerarin groups. Results: In the TBI model, Puerarin treatment reduced brain injury, inflammation, neurological deficits, and brain water content in TBI mice and reversed the TBI-induced expression changes of the four key genes at both mRNA and protein levels. Conclusions: Puerarin may protect against TBI by targeting ferroptosis-related pathways, with core genes NQO1, VCP, PML and RELA playing key roles. It may also modulate immune cell infiltration through these targets, contributing to its therapeutic effects.