The study investigates the role of ketone bodies, specifically β-hydroxybutyrate (BHB), in regulating the NLRP3 inflammasome, a key player in innate immune responses. BHB, but not other ketone bodies or short-chain fatty acids, suppresses NLRP3 activation in response to various stimuli without affecting other inflammasomes. Mechanistically, BHB inhibits NLRP3 by preventing K⁺ efflux and reducing ASC oligomerization and speck formation. This inhibition is independent of classical starvation mechanisms like AMPK, ROS, autophagy, or glycolysis. In vivo studies in mouse models of NLRP3-mediated diseases show that BHB reduces caspase-1 activation and IL-1β secretion. The findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB's inhibition of the NLRP3 inflammasome, highlighting potential therapeutic applications for interventions that elevate BHB levels to treat NLRP3-mediated inflammatory diseases.The study investigates the role of ketone bodies, specifically β-hydroxybutyrate (BHB), in regulating the NLRP3 inflammasome, a key player in innate immune responses. BHB, but not other ketone bodies or short-chain fatty acids, suppresses NLRP3 activation in response to various stimuli without affecting other inflammasomes. Mechanistically, BHB inhibits NLRP3 by preventing K⁺ efflux and reducing ASC oligomerization and speck formation. This inhibition is independent of classical starvation mechanisms like AMPK, ROS, autophagy, or glycolysis. In vivo studies in mouse models of NLRP3-mediated diseases show that BHB reduces caspase-1 activation and IL-1β secretion. The findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB's inhibition of the NLRP3 inflammasome, highlighting potential therapeutic applications for interventions that elevate BHB levels to treat NLRP3-mediated inflammatory diseases.