Post-translational modifications of gasdermin D: implications for pyroptosis and autoimmune diseases

Gasdermin D (GSDMD) is a key executioner of pyroptosis, a lytic and pro-inflammatory form of programmed cell death that supports host defense but can also drive autoimmune and inflammatory pathology. While proteolytic cleavage is necessary to generate the pore-forming GSDMD N-terminal (GSDMD-NT) fragment, accumulating evidence indicates that post-translational modifications (PTMs)-including phosphorylation, ubiquitination, palmitoylation and acetylation-create an additional "execution-control" layer that tunes membrane targeting, oligomerization, stability and signal termination. Nevertheless, PTM-resolved regulation of GSDMD remains incompletely mapped. Accordingly, systematic validation in human-relevant systems and cell-type-resolved PTM profiling will be essential for translation. In this review, we synthesize current knowledge of GSDMD PTMs and integrate them into a hierarchical, spatiotemporal framework spanning initiation, membrane licensing, checkpoint inhibition and clearance. We further connect PTM mechanisms to representative disease contexts, including sepsis/endotoxemia, systemic lupus erythematosus and inflammatory bowel disease, to illustrate how shifts between "licensing" and "clearance" can shape tissue injury while potentially affecting host defense. Finally, we summarize emerging small-molecule modulators that target this PTM layer (e.g., palmitoylation and ubiquitination axes), discuss translational opportunities and limitations, and outline experimental priorities for PTM-based therapeutic development.