Interplay of cell death pathways and immune responses in ischemic stroke: insights into novel biomarkers

Abstract Stroke is a severe neurological disease and a major worldwide issue, mostly manifesting as ischemic stroke (IS). In order to create effective treatments for IS, it is imperative to fully understand the underlying pathologies, as the existing therapeutic choices are inadequate. Recent investigations have shown the complex relationships between several programmed cell death (PCD) pathways, including necroptosis, ferroptosis, and pyroptosis, and their correlation with immune responses during IS. However, this relationship is still unclear. To address this gap, this review study explored the cellular interactions in the immune microenvironment of IS. Then, to validate prior findings and uncover biomarkers, the study investigated bioinformatics studies. Several pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Toll-like receptor 4 (TLR4), and receptor-interacting protein kinase (RIPK), were involved in PCD-immune interactions. The bioinformatics studies reported key biomarkers such as glutathione peroxidase 4 (GPX4), NOD-like receptor family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD), and TLR4, which have important implications in ferroptosis, cuproptosis, pyroptosis, and necroptosis respectively. These biomarkers were associated with PCD mechanisms such as oxidative stress and inflammatory reactions. The immune infiltration analysis consistently revealed a significant correlation between PCD pathways and detrimental immune cells, such as neutrophils and γδ T cells. Conversely, M2 macrophages and T helper cells showed protective effects. In conclusion, considering the intricate network of interactions between immune responses and PCD pathways, this study emphasized the necessity of a paradigm shift in therapeutic approaches to address the injuries that are related to this complex network.