Aspirin mitigates sepsis-associated encephalopathy by modulating ICAM-1 and MMP-9 signaling: Evidence from clinical cohorts and mechanistic experiments.

Sepsis-associated encephalopathy (SAE) is a devastating complication contributing substantially to intensive care unit mortality and long-term cognitive impairment. Although observational studies suggest that aspirin use was associated with reduced sepsis-related mortality, its neuroprotective potential against SAE and underlying molecular mechanisms remain unclear. Using data from the Medical Information Mart for Intensive Care IV and eICU Collaborative Research Database, we demonstrated through propensity score matching and inverse probability of treatment weighting that aspirin use was significantly associated with reduced SAE incidence without increased gastrointestinal bleeding risk. Meta-analysis yielded a pooled protective association (OR 0.69, 95% CI 0.57-0.83) with moderate heterogeneity (I2 = 63.6%). Transcriptomic profiling of hippocampal tissues from lipopolysaccharide (LPS)-induced SAE mice revealed intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) as aspirin-responsive hub genes enriched in leukocyte adhesion and extracellular matrix remodeling pathways. In murine models, aspirin significantly improved cognitive performance in novel object recognition and Y-maze tests, while reducing anxiety-like behavior. Mechanistically, aspirin suppressed LPS-induced upregulation of ICAM-1 and MMP-9 expression in hippocampus and prefrontal cortex, preserved blood-brain barrier integrity by restoring tight junction-related and adherens junction-related proteins reducing Evans blue extravasation, attenuated neuroinflammatory signaling through decreased cyclooxygenase-2, nuclear factor-κB, tumor necrosis factor-α, interleukin-6, and prostaglandin E2 expression, and reduced cleaved caspase-3-mediated neuronal apoptosis. These findings provide convergent evidence that aspirin mitigates SAE through suppression of ICAM-1 and MMP-9-associated inflammatory and endothelial dysfunction, supporting its potential as a neuroprotective adjunctive therapy and identifying ICAM-1 and MMP-9 as promising therapeutic targets for SAE.