GSDMD-mediated pyroptosis: molecular mechanisms, diseases and therapeutic targets

Abstract Pyroptosis is a regulated form of inflammatory cell death in which Gasdermin D (GSDMD) plays a central role as the key effector molecule. GSDMD-mediated pyroptosis is characterized by complex biological features and considerable heterogeneity in its expression, mechanisms, and functional outcomes across various tissues, cell types, and pathological microenvironments. This heterogeneity is particularly pronounced in inflammation-related diseases and tumors. In the context of inflammatory diseases, GSDMD expression is typically upregulated, and its activation in macrophages, neutrophils, T cells, epithelial cells, and mitochondria triggers both pyroptotic and non-pyroptotic pathways, leading to the release of pro-inflammatory cytokines and exacerbation of tissue damage. However, under certain conditions, GSDMD-mediated pyroptosis may also serve a protective immune function. The expression of GSDMD in tumors is regulated in a more complex manner, where it can either promote immune evasion or, in some instances, induce tumor cell death. As our understanding of GSDMD's role continues to progress, there have been advancements in the development of inhibitors targeting GSDMD-mediated pyroptosis; however, these therapeutic interventions remain in the preclinical phase. This review systematically examines the cellular and molecular complexities of GSDMD-mediated pyroptosis, with a particular emphasis on its roles in inflammation-related diseases and cancer. Furthermore, it underscores the substantial therapeutic potential of GSDMD as a target for precision medicine, highlighting its promising clinical applications.