S100a9 Aggravates Ischemia Brain Injury via Pyroptosis Pathway: A Potential Prognostic Biomarker and Therapeutic Target for Ischemic Stroke

Ischemic stroke, a leading cause of global morbidity and disability, involves incompletely elucidated pathophysiological mechanisms. Emerging evidence highlights pyroptosis-an inflammatory programmed cell death pathway-as a critical contributor to ischemic brain injury progression. The pro-inflammatory mediator S100a9 may exacerbate neuronal damage through Pyroptosis regulation, prompting this investigation into its role in post-stroke outcomes and underlying mechanisms. We employed a multi-modal approach integrating public omics datasets, clinical cohorts, murine middle cerebral artery occlusion (MCAO) models, and cellular oxygen-glucose deprivation/reperfusion (OGD/R) systems to delineate expression patterns of S100a9 and pyroptosis-associated biomarkers. Pharmacological targeting of S100a9 using Paquinimod and siRNA-mediated knockdown further defined its functional regulation of pyroptotic cascades. Results demonstrate that S100a9 amplifies neuroinflammatory responses and microglia-specific Pyroptosis, correlating with worsened infarct volumes and poor 30-day modified Rankin Scale scores. Targeted S100a9 inhibition attenuated brain injury and neuroinflammation, highlighting its potential as a therapeutic target for stroke intervention.

S100a9; ischemic stroke; neuroinflammation; pyroptosis.