Various post-translational modifications (PTMs), such as palmitoylation, acetylation, and ubiquitination, have been shown to regulate pyroptosis. However, the role of small ubiquitin-like modifier (SUMO) modification, known as SUMOylation, in regulating GSDMD activity and pyroptosis remains unclear. Here, we demonstrate that inhibition of SUMOylation reduces inflammatory pyroptosis by downregulating GSDMD expression. Identification of key SUMOylation sites on GSDMD-K177, is critical for regulates pyroptosis. Furthermore, we identify SENP3 as a critical deSUMOylating enzyme that binds to GSDMD, suppressing GSDMD SUMO modification, which destabilizes GSDMD and inhibits LDH secretion. These findings highlight the role of SUMOylation in GSDMD mediated-pyroptosis, suggesting SUMO inhibitors as potential therapies for inflammatory diseases.
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