Scientists discovered that a skin protein called GSDMA gets a fatty tag (S‑acylation) which helps it cause a type of cell death called pyroptosis. This tagging helps the protein stick to membranes and form groups, and a different enzyme can remove the tag. The findings are mostly about basic cell biology and don’t give any direct health or performance advice.

GSDMA, the primary member of the gasdermin family found in the skin, is critical for pathogen-induced pyroptosis during infection. Recent studies revealed that another gasdermin, GSDMD, undergoes palmitoylation during pyroptosis. However, whether and how the other gasdermin members undergo lipid modification remains poorly understood. Here, we demonstrate that GSDMA is <i>S</i>-acylated at the conserved cysteine residues in its N-terminal domain. We show that <i>S</i>-acylation of GSDMA promotes pyroptosis by facilitating its membrane anchoring and protein oligomerization, a mechanism distinct from the palmitoylation of GSDMD at the N-terminal C191 residue. Additionally, we present evidence that recombinant proteins of GSDMA and GSDMD can undergo <i>S</i>-acylation <i>in vitro</i> via direct interaction with palmitoyl-CoA, suggesting they potentially possess auto-acylation capacity. Furthermore, we identify ABHD17A as one of the deacylating enzymes that regulate the dynamic fatty acylation cycle of GSDMA. Overall, our studies reveal new molecular mechanisms underlying GSDMA function through S-acylation and underscore its important role in regulating pyroptosis mediated by GSDMA.