Gasdermin D: a key mediator of inflammation in cardiovascular disease with a focus on atherosclerosis

Gasdermin D (GSDMD) has been identified as a potential key effector protein within the inflammatory response and is characterized as a primary executor of pyroptosis through the formation of transmembrane pores. This review evaluates the emerging role of GSDMD-mediated pyroptosis in the pathogenesis of cardiovascular diseases (CVDs), with a specific focus on its potential contributions to atherosclerosis. We examine how the activation of GSDMD by inflammasomes, such as NLRP3 and AIM2, facilitates the release of inflammatory cytokines (IL-1β and IL-18) and damage-associated molecular patterns (DAMPs). Central to this discussion is the proposed role of GSDMD in driving macrophage foam cell death and vascular smooth muscle cell (VSMC) dysfunction. These factors are associated with necrotic core expansion and increased risk of atherosclerotic plaque instability. Furthermore, GSDMD may mediate endothelial dysfunction and disrupt lipid metabolism, and is suggested to participate in systemic signaling via extracellular vesicles. Finally, we highlight the therapeutic potential of targeting GSDMD as a possible strategy to stabilize vulnerable plaques, which may offer new avenues for cardiovascular precision medicine.