International immunopharmacology · 2025
DDX3X could regulate gouty inflammation via NLRP3 Inflammasome activation and macrophage Pyroptosis crosstalk.
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Zhong Linrui, Lei Tianyi, Guo Jianwei, Zheng Jianxiong, Wang Shunbing, Ming Bin, Wang Yang, Zhang Quanbo, Qing Yufeng
Аннотация
OBJECTIVE: Pyroptosis is implicated in acute flares and spontaneous remission of gout, but its specific regulatory mechanisms remain unclear. This study aimed to explore the potential role of DEAD-box helicase 3 X-linked (DDX3X) as a hub molecule influencing pyroptosis to regulate gouty inflammation.
METHODS: Bioinformatics analysis was employed to identify pyroptosis and gout associated genes and their potential connections. Macrophage (THP-1) was stimulated (0, 3, 6, 9, 12 h) with MSU crystals to construct a gouty inflammation model. DDX3X, IL-1β and classical pyroptosis pathway molecules was measured. ROS levels and colocalization of DDX3X and NLRP3 were assessed by immunofluorescence. To determine the effects of DDX3X on pyroptosis and gouty inflammation, the key genes of pyroptosis and IL-1β were detected by Western blot following DDX3X knockdown and overexpression.
RESULTS: Bioinformatics confirmed the participation of pyroptosis in gout and identified nine Gout-PRGs. Correlation analysis of these nine Gout-PRGs showed that DDX3X was closely linked to NLRP3. Validation demonstrated elevated DDX3X expression in PBMCs from AG patients. In an in vitro gouty inflammation model, the expression of classical pyroptosis pathway molecules and DDX3X both exhibited significant nonlinear characteristics and showed parallel trends to ROS accumulation and IL-1βexpression. Immunofluorescence results showed a clear colocalization between DDX3X and NLRP3. Following DDX3X knockdown and overexpression in the early (3 h) and late (9 h) stages of oxidative stress, NLRP3, IL-1β and pyroptosis molecules both showed a Characteristic change.
CONCLUSION: DDX3X could regulate gouty inflammation by activating the NLRP3 inflammasome and mediating macrophage pyroptosis.
METHODS: Bioinformatics analysis was employed to identify pyroptosis and gout associated genes and their potential connections. Macrophage (THP-1) was stimulated (0, 3, 6, 9, 12 h) with MSU crystals to construct a gouty inflammation model. DDX3X, IL-1β and classical pyroptosis pathway molecules was measured. ROS levels and colocalization of DDX3X and NLRP3 were assessed by immunofluorescence. To determine the effects of DDX3X on pyroptosis and gouty inflammation, the key genes of pyroptosis and IL-1β were detected by Western blot following DDX3X knockdown and overexpression.
RESULTS: Bioinformatics confirmed the participation of pyroptosis in gout and identified nine Gout-PRGs. Correlation analysis of these nine Gout-PRGs showed that DDX3X was closely linked to NLRP3. Validation demonstrated elevated DDX3X expression in PBMCs from AG patients. In an in vitro gouty inflammation model, the expression of classical pyroptosis pathway molecules and DDX3X both exhibited significant nonlinear characteristics and showed parallel trends to ROS accumulation and IL-1βexpression. Immunofluorescence results showed a clear colocalization between DDX3X and NLRP3. Following DDX3X knockdown and overexpression in the early (3 h) and late (9 h) stages of oxidative stress, NLRP3, IL-1β and pyroptosis molecules both showed a Characteristic change.
CONCLUSION: DDX3X could regulate gouty inflammation by activating the NLRP3 inflammasome and mediating macrophage pyroptosis.