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Abstract The NLRP3 inflammasome is a central mediator of metabolic inflammation, yet the upstream mechanisms remain poorly defined. We identified RGS10 as a critical regulator of NLRP3-driven immunometabolic responses. In macrophages, loss of RGS10 enhanced calcium-dependent NLRP3 inflammasome activity during both priming and activation. In high-fat diet-fed male mice, Nlrp3 deletion improved glucose tolerance, adipose remodeling, and hepatic and hypothalamic pathology, whereas Rgs10 deletion induced the opposite phenotype. These benefits required RGS10: in Nlrp3 -/-/ Rgs10 -/- (dKO) males, the improvements in glucose tolerance, adipose remodeling, and hypothalamic microgliosis were abolished. This requirement was selective; RGS10 acted dominantly to restrain myeloid and hepatic inflammation independent of NLRP3, and the interaction was sex-dependent. Finally, RGS10 declined in aged and Parkinson’s disease human microglia, and aged Rgs10 -/- mice developed glucose intolerance. Together, these findings establish RGS10 as a dominant, sex-dependent upstream regulator of NLPR3-driven inflammation, suggesting that age- or inflammation-associated RGS10 loss may limit the efficacy of NLRP3-targeted therapies.
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