Targeting the gasdermin D as a strategy for ischemic stroke therapy

Stroke is a major cause of death and disability worldwide that triggers a variety of neuropathological conditions, leading to the initiation of several pro-inflammatory mediators and neuronal damage. Neuroinflammation has been considered the potential therapeutic target and contributes to the pathology of ischemia and reperfusion. Pyroptosis is an inflammatory form of programmed cell death that plays an important role in immune protection against stroke. Gasdermin D (GSDMD) is the final executor of pyroptosis upon cleavage by caspases-1/4/5/11, followed by canonical and noncanonical inflammasome activation, leading to a series of inflammatory responses. GSDMD N-terminal domain assembles plasma membrane as well as organelle membrane pores to induce cytolysis, thereby triggering cytokine release and inflammatory-related cell death. In our review, we concisely summarized and highlighted the potential role of GSDMD-regulated pyroptosis and the biological characteristic of GSDMD as a therapeutic target in ischemic stroke. A better understanding of the roles of GSDMD may provide a theoretical basis for the design of novel therapeutic interventions for the treatment of ischemic stroke.