Post-translational modifications (PTMs) play a critical role in regulating NLRP3 inflammasome signaling, assembly, and cell death. These modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation, influence inflammasome activity by affecting protein-protein interactions, stability, and localization. Dysregulation of these modifications is linked to inflammatory diseases, highlighting their importance in maintaining proper inflammasome function. NLRP3, the central component of the inflammasome, undergoes various PTMs. Phosphorylation at specific sites, such as Ser-5 and Ser-198, modulates NLRP3's interaction with other inflammasome components, affecting its activation and assembly. Phosphorylation by AKT, JNK, and Pak1 can either inhibit or promote inflammasome activity. Similarly, ubiquitination and SUMOylation regulate NLRP3's stability and localization, with different ubiquitin linkages (K48 vs. K63) having distinct functional roles. For example, K63-linked ubiquitination promotes ASC oligomerization and inflammasome activation, while K48-linked ubiquitination targets NLRP3 for degradation. ASC, an adaptor protein in the inflammasome, is also modified by PTMs. Phosphorylation and ubiquitination of ASC influence its oligomerization and speck formation, which are essential for caspase-1 activation and IL-1β release. The E3 ligase Pellino-1 promotes K63-linked ubiquitination of ASC, enhancing its interaction with NLRP3. TRAF3 also contributes to ASC ubiquitination, supporting inflammasome activation. Caspase-1, activated by the inflammasome, undergoes autocleavage and cleaves GSDMD, leading to pyroptosis. Caspase-1 is also modified by PTMs, including ubiquitination and S-nitrosylation, which can inhibit its activity. GSDMD, the executor of pyroptosis, is modified by phosphorylation, succination, and palmitoylation, all of which affect its pore-forming ability and cell death. IL-1β, a key cytokine released during inflammasome activation, is regulated by PTMs such as S-glutathionylation and ubiquitination. These modifications influence IL-1β stability and activity, impacting inflammatory responses. Despite significant progress, many questions remain about the integration and coordination of PTMs in the inflammasome pathway. Understanding how these modifications interact and regulate inflammasome function is crucial for developing therapeutic strategies for inflammatory diseases.Post-translational modifications (PTMs) play a critical role in regulating NLRP3 inflammasome signaling, assembly, and cell death. These modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation, influence inflammasome activity by affecting protein-protein interactions, stability, and localization. Dysregulation of these modifications is linked to inflammatory diseases, highlighting their importance in maintaining proper inflammasome function. NLRP3, the central component of the inflammasome, undergoes various PTMs. Phosphorylation at specific sites, such as Ser-5 and Ser-198, modulates NLRP3's interaction with other inflammasome components, affecting its activation and assembly. Phosphorylation by AKT, JNK, and Pak1 can either inhibit or promote inflammasome activity. Similarly, ubiquitination and SUMOylation regulate NLRP3's stability and localization, with different ubiquitin linkages (K48 vs. K63) having distinct functional roles. For example, K63-linked ubiquitination promotes ASC oligomerization and inflammasome activation, while K48-linked ubiquitination targets NLRP3 for degradation. ASC, an adaptor protein in the inflammasome, is also modified by PTMs. Phosphorylation and ubiquitination of ASC influence its oligomerization and speck formation, which are essential for caspase-1 activation and IL-1β release. The E3 ligase Pellino-1 promotes K63-linked ubiquitination of ASC, enhancing its interaction with NLRP3. TRAF3 also contributes to ASC ubiquitination, supporting inflammasome activation. Caspase-1, activated by the inflammasome, undergoes autocleavage and cleaves GSDMD, leading to pyroptosis. Caspase-1 is also modified by PTMs, including ubiquitination and S-nitrosylation, which can inhibit its activity. GSDMD, the executor of pyroptosis, is modified by phosphorylation, succination, and palmitoylation, all of which affect its pore-forming ability and cell death. IL-1β, a key cytokine released during inflammasome activation, is regulated by PTMs such as S-glutathionylation and ubiquitination. These modifications influence IL-1β stability and activity, impacting inflammatory responses. Despite significant progress, many questions remain about the integration and coordination of PTMs in the inflammasome pathway. Understanding how these modifications interact and regulate inflammasome function is crucial for developing therapeutic strategies for inflammatory diseases.