<p>Ischemic stroke remains a leading cause of morbidity and mortality worldwide. Current therapeutic approaches for ischemic stroke are limited, particularly in targeting the interconnected mechanisms of neuroinflammation and oxidative stress. There is a critical need for effective neuroprotective agents that address these pathways to mitigate I/R-induced injury. Here, we used bioinformatics analysis to identify differentially expressed genes (DEGs) associated with ischemic stroke and performed enrichment analysis to uncover hub genes and signaling pathways central to disease progression. MG-132, a proteasome inhibitor, was identified as a promising candidate and investigated for its neuroprotective efficacy in middle cerebral artery occlusion/reperfusion (MCAO/R) models. MG-132 treatment significantly reduced infarct size, decreased cerebral edema, and improved neurological outcomes. Mechanistically, MG-132 downregulated PTGS2 expression, inhibited NF-κB activation, and reduced pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17. Furthermore, MG-132 alleviated oxidative stress and apoptosis, as evidenced by decreased malondialdehyde (MDA) levels and fewer TUNEL-positive cells. These findings demonstrate that MG-132 exerts robust neuroprotection by modulating the PTGS2/NF-κB signaling pathway, addressing key pathological processes in I/R injury. This study provides a foundation for developing targeted therapeutic strategies that mitigate neuroinflammation and oxidative stress in ischemic stroke, advancing the search for effective interventions in this critical area of unmet medical need.</p> Graphical Abstract <p></p>