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.
Qi et al. (Wed,) studied this question.