Background/Purpose: Pyroptosis is closely linked to acute flare-ups and spontaneous remission of gout. However, the specific mechanisms by which pyroptosis regulates gout inflammation remain unclear. This study aims to analyze the potential role of DDX3X as a hub molecule influencing pyroptosis to regulate gout inflammation.

Methods: Bioinformatics methods were used to explore whether pyroptosis is involved in regulating gout. Real-time quantitative PCR (RT-qPCR), Western blotting (WB), and immunofluorescence were employed to assess DDX3X, ROS levels, and changes in the NLRP3/Caspase-1/GSDMD pathway. The regulation of pyroptosis mediated by DDX3X under different conditions was observed.

Results: Bioinformatics analysis revealed that pyroptosis is involved in gout regulation, identifying nine （pyroptosis-related genes）PRGs with DDX3X closely related to NLRP3. DDX3X was significantly overexpressed in acute gout patients. In the time-gradient model of gout inflammatory cells, both the classical pyroptosis pathway and DDX3X showed significant nonlinear characteristics, leading to trends in IL-1β changes, with DDX3X interacting with NLRP3. After DDX3X expression intervention, pyroptosis and gout inflammation showed characteristic changes. At the 3h oxidative damage stage, DDX3X participated in activating the NLRP3 inflammasome to promote pyroptosis. At the 9h oxidative stress stage, DDX3X might respond to stress granule assembly, indirectly inhibiting pyroptosis, thereby protecting cell survival. This protective mechanism might initiate negative feedback regulation to inhibit IL-1β release.

Conclusion: DDX3X can regulate gout inflammation by activating the NLRP3 inflammasome and mediating macrophage pyroptosis. It mainly participates in early inflammation in gout and cell homeostasis maintenance in the later stages of inflammation.

Figure1. DDX3X and pyroptosis play an important role in gout inflammation

Figure2. DDX3X and pyroptosis were differentially expressed in gout and were closely related to inflammation levels and oxidative stress

Figure2. DDX3X contributes to gout inflammation by mediating pyroptosis through modulating NLRP3 inflammasome assembly

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ddx3x-regulates-gout-inflammation-via-nlrp3-inflammasome-activation-and-macrophage-pyroptosis-crosstalk/