Gasdermin D in Neurodegenerative Diseases: Pathogenic Roles and Therapeutic Perspectives.

Gasdermin D (GSDMD) is the executioner of pyroptosis, a form of inflammatory programmed cell death. The GSDMD N-terminal domain inserts into the plasma membrane, where it oligomerizes to form pores, leading to membrane rupture and the release of pro-inflammatory mediators. Beyond its role in pyroptosis, GSDMD can hyperactivate inflammatory signaling in living cells and also participates in neutrophil extracellular traps (NETs) formation. Therefore, GSDMD can serve as a trigger for chronic inflammation. Neurodegenerative diseases (NDDs) are characterized by progressive neuronal loss, and accumulating evidence has linked neuroinflammation and pyroptosis to their pathogenesis, with brain-resident immune cells playing a central role. Targeting pyroptosis, particularly via GSDMD, may therefore represent a novel therapeutic strategy for NDDs. In this review, we highlight the cell-type specificity of GSDMD expression and its pathogenic roles across different NDD models. We further discuss the emerging therapeutic potential of GSDMD inhibition and summarize the known GSDMD inhibitors that have been evaluated in NDD models. By providing a comprehensive overview of GSDMD in NDD pathophysiology and exploring its therapeutic implications, this review aims to advance both our understanding of NDD mechanisms and the development of novel treatment strategies.