IL-6 and TNF-α in Ischemic Stroke: A Cardiogenetic Perspective on Inflammation and Clinical Outcomes

Background: Ischemic stroke (IS) is a major cause of global disability, with outcomes increasingly dictated by post-ischemic neuroinflammation. Despite advances in reperfusion, many patients experience neurological decline due to divergent inflammatory responses. Objectives: This review synthesizes current evidence on inflammatory signaling, stroke genetics, and genetically informed precision medicine relevant to the interplay between interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and ischemic stroke outcomes. Methods: We reviewed evidence from genome-wide association studies, Mendelian randomization analyses, experimental studies, observational biomarker cohorts, and relevant cardiovascular anti-inflammatory trials. Evidence from non-stroke populations is identified as indirect and is not interpreted as proof of efficacy in ischemic stroke. Results: IL-6 and TNF-α signaling involves receptor- and context-dependent mechanisms that may have both harmful and protective effects after cerebral ischemia. Multi-omic studies of the chromosome 9p21 locus and ANRIL suggest potential links among vascular-cell regulation, inflammation, and atherosclerotic risk, although stroke-specific mechanistic evidence remains limited. Elevated inflammatory-marker concentrations have been associated with greater stroke severity and unfavorable outcomes; however, their independent prognostic value and optimal sampling strategy require further validation. Selective anti-inflammatory approaches provide biologically plausible strategies for future study, but genotype-guided anti-cytokine treatment is not established for acute ischemic stroke or post-stroke recovery. Conclusions: Stroke genetics and multi-omic approaches may contribute to future precision-medicine strategies, but their clinical utility requires validation in prospective, stroke-specific studies. Current evidence does not support routine cytokine genotyping or genotype-guided anti-cytokine treatment in ischemic stroke.