Pyroptosis in epilepsy: from pathophysiological mechanisms to therapeutic strategies

Epilepsy affects millions of individuals worldwide, however, approximately one-third of patients exhibit pharmacoresistance to currently available antiseizure therapies, underscoring an urgent unmet need for novel mechanism-based therapeutic strategies. Pyroptosis, a Gasdermin-mediated proinflammatory cell death, has recently been implicated as a pivotal driver of epileptogenesis and disease progression. This narrative critically evaluates emerging preclinical and clinical evidence linking pyroptotic signaling to epilepsy pathophysiology, with particular attention to cell-type-specific contributions. In astrocytes, GSDMD activation compromises blood-brain barrier (BBB) integrity, an effect mediated by the downregulation of endothelial tight junction proteins. In neurons, activation of the TRPM7/ROS/JAK2/STAT3 pathway drives pyroptosis, a process that also involves the interaction between NLRP3 and mitophagy. Microglial pyroptosis amplifies neuroinflammation, creating a self-perpetuating cycle. Clinically, the caspase-1 inhibitor VX-765 demonstrated favorable safety and preliminary efficacy in a Phase II randomized controlled trial in patients with refractory epilepsy; however, the trial did not meet its primary efficacy endpoint, suggesting that longer treatment durations may be required to assess its therapeutic potential. Preclinically, the GSDMD inhibitor disulfiram shows BBB-protective effects but is limited by off-target hepatotoxicity; conversely, development of the NLRP3 inhibitor MCC950 was discontinued following adverse hepatic findings in early clinical studies. Accumulating evidence also suggests that non-canonical pyroptotic pathways (caspase-4/5/11, GSDME) and PANoptosis, which integrates pyroptosis, apoptosis, and necroptosis, play a role in epileptic neuronal death. Major translational hurdles poor CNS bioavailability of candidate inhibitors, compensatory activation of parallel cell death pathways, and the absence of validated, clinically actionable biomarkers. Future efforts should therefore focus on developing cell-selective pyroptosis modulators, advanced CNS-targeted delivery platforms (e.g., nanoparticle- or antibody-conjugated systems), and biomarker-informed patient enrichment strategies to enable rational clinical translation of pyroptosis-directed therapeutics.