Gasdermins in neurodegeneration: emerging mechanisms and therapeutic targets

Abstract Gasdermins (GSDM) are pore-forming proteins that mediate pyroptosis, an inflammatory form of programmed cell death characterized by membrane permeabilization and the release of intracellular contents. Beyond their roles in host defense and immunity, recent studies have revealed critical contributions of GSDMs, particularly GSDMD and GSDME, to the pathogenesis of neurodegenerative disorders. Their functional scope has now expanded beyond executing cell death to roles in tissue regeneration and food tolerance. The recent discovery that intact, full-length GSDMs can form pores is prompting a reevaluation of long-standing models of gasdermin activation. How post-transcriptional modifications (PTMs) regulate this unconventional activity, and under what physiological or pathological contexts these alternative mechanisms are engaged, remains an open question. Moreover, the development of neutralizing biologics that specifically target GSDM pores opens new avenues for therapeutic intervention. In light of these emerging insights, this review will provide a comprehensive and up-to-date overview of recent breakthroughs in GSDM research. We highlight advances in the structural basis of GSDM activation and pore assembly. We also discuss how these mechanisms are involved in the pathogenesis of neurodegenerative diseases and therapeutic strategies based on the emerging small-molecule inhibitors and neutralizing biologics.