The Caspase‐1/GSDMD/PXN/VCAM‐1 Cascade Mediates Cerebral Ischemia–Reperfusion Injury

Pyroptosis, as an inflammatory type of regulated cell death, is associated with the pathogenesis of various inflammatory diseases. Targeted therapy for pyroptosis has shown promise in multiple preclinical models of neurological injury and disorders. Stroke is one of the leading causes of morbidity and mortality worldwide and the top cause of disease-related death in China. Although the pyroptosis signaling pathway has been studied in cerebral ischemic diseases, its pathophysiological mechanisms in brain microvascular endothelial cells (BMECs) remain unclear. In this study, we demonstrate that pyroptosis levels in BMECs are significantly elevated under ischemia-reperfusion (I/R) conditions and are closely associated with extensive macrophage infiltration in the brain, leading to inflammatory injury. We observed that the caspase-1 signaling pathway mediates GSDMD-dependent VCAM-1 expression, promoting the adhesive interaction between reactive endothelial cells and macrophages, thereby exacerbating the inflammatory microenvironment in the brain. Furthermore, omics analysis revealed that, upon caspase-1 activation, phosphorylated PXN (p-PXN) facilitates VCAM-1-mediated adhesion upstream, amplifying the inflammatory cascade and aggravating cerebral ischemic injury. In summary, our findings highlight the potential of non-glial and non-neuronal cells in amplifying neuroinflammation, providing additional theoretical support for the treatment of ischemic brain injury.