Abstract
BACKGROUND: Post-stroke cognitive impairment (PSCI) is a prevalent complication that impairs stroke survivors' quality of life and rehabilitation. Growing evidence highlights the crucial role of inflammation in PSCI pathogenesis. The tumor necrosis factor (TNF) signaling pathway, especially tumor necrosis factor-α (TNF-α), has gained attention for its role in neuroinflammatory diseases. TNF pathway activation is strongly associated with neuronal injury and neuroinflammation in stroke, suggesting its involvement in PSCI. However, the exact mechanisms by which TNF signaling contributes to PSCI remain unclear. OBJECTIVE: This review summarizes recent evidence on the TNF signaling pathway to elucidate its molecular mechanisms, analyze its role in PSCI pathogenesis, and examine associated inflammatory responses and their functional consequences. We also explores potential therapeutic targets, offering novel perspectives for PSCI intervention. METHODS: A comprehensive literature search was conducted across electronic databases including PubMed, Web of Science, Embase, and MEDLINE to identify relevant studies. We systematically reviewed recent research investigating the role and mechanisms of the TNF signaling pathway in PSCI. Eligible studies were rigorously screened, followed by data extraction and quality assessment using standardized criteria. CONCLUSIONS: The TNF signaling pathway is complex and heterogeneous in PSCI, potentially attributable to variations in study designs, samples, experimental models, and interventions. Emerging evidence supports the therapeutic potential of pharmacological and biological agents targeting this pathway. These findings highlight the need for integrated clinical and basic research to strengthen the foundation for early diagnosis, prevention, and treatment of PSCI, and to guide evidence-based clinical decisions.