Tingting Qi, Zhen Xiao, Yufeng Peng, Yinjuan Zhou, Wen Wang, Changxi Li, Jinhao Kang, Tingting Zhao, Guoming Mao, Yujie Weng, Haiping Wei
Ischemic stroke, a leading cause of neurological disability and mortality, involves a multifactorial cascade of oxidative stress, mitochondrial dysfunction, and inflammation. Yet, conventional paradigms centered on apoptosis and necrosis fail to fully explain the inflammatory amplification that drives secondary brain injury-underscoring the emerging significance of pyroptosis as a distinct and targetable death program. This review delineates the mechanistic architecture of pyroptosis in ischemic stroke, integrating canonical (NLRP3-caspase-1-GSDMD) and noncanonical (caspase-4/5/11-GSDMD) inflammasome cascades with apoptosis-, necroptosis-, and ferroptosis-linked pathways within a unified PANoptotic continuum. Upstream regulators-such as mitochondrial ROS-TXNIP coupling, STING-mediated innate immune signaling, and astrocytic LCN2/24p3R activation-coordinate oxidative stress with neuroinflammatory propagation and blood-brain barrier disruption. Pharmacological inhibition of inflammasomes (MCC950, CY-09, OLT1177), caspases (VX-765, Ac-YVAD-CMK), or gasdermins (disulfiram, necrosulfonamide) markedly reduces IL-1β/IL-18 release and preserves neurovascular integrity in preclinical models, highlighting pyroptosis as a therapeutically tractable axis in ischemic stroke. Despite these advances, challenges remain in defining temporal-cellular specificity and achieving clinical translation. Integrating single-cell multi-omics, spatial imaging, and nanocarrier-based delivery systems may enable precise, phase-adaptive modulation of pyroptosis, transforming destructive inflammation into controlled neurovascular recovery.