The NALP3 inflammasome is activated by low intracellular potassium (K⁺) concentrations, while the IPAF inflammasome is not. This study shows that inhibiting K⁺ efflux blocks NALP3 inflammasome activation but not IPAF. Low intracellular K⁺ is also required for NALP1 inflammasome activation by Bacillus anthracis lethal toxin. In vitro, NALP inflammasome assembly and caspase-1 recruitment occur spontaneously at K⁺ concentrations below 90 mM, but are prevented at higher concentrations. Thus, low intracellular K⁺ may be the least common trigger of NALP inflammasome activation. The NALP3 inflammasome is activated by various microbial and host-derived molecules, including bacterial components, toxins, and DAMPs. These activators induce intracellular K⁺ efflux, which is essential for caspase-1 activation. ATP and nigericin act through a K⁺-dependent mechanism. The study demonstrates that extracellular K⁺ inhibits NALP3 inflammasome activation in human monocytes. Physiological intracellular K⁺ concentrations inhibit inflammasome assembly, suggesting that K⁺ efflux is a common trigger for NALP3 and NALP1 inflammasome activation. The mechanism by which K⁺ efflux induces inflammasome activation is not fully understood, but reactive oxygen species (ROS) may play a role. The data suggest that a decrease in intracellular K⁺ concentration is a common trigger for NALP3 inflammasome activation. This model is supported by the observation that some of the most potent activators of the NALP3 inflammasome are K⁺ channels. The study also highlights the role of K⁺ in the regulation of inflammation and the potential involvement of K⁺ channels in inflammasome activation. The findings suggest that K⁺ efflux is a common and specific trigger for NALP1 and NALP3 inflammasome activation, and that the exact nature and mode of activation of these channels remain to be identified.The NALP3 inflammasome is activated by low intracellular potassium (K⁺) concentrations, while the IPAF inflammasome is not. This study shows that inhibiting K⁺ efflux blocks NALP3 inflammasome activation but not IPAF. Low intracellular K⁺ is also required for NALP1 inflammasome activation by Bacillus anthracis lethal toxin. In vitro, NALP inflammasome assembly and caspase-1 recruitment occur spontaneously at K⁺ concentrations below 90 mM, but are prevented at higher concentrations. Thus, low intracellular K⁺ may be the least common trigger of NALP inflammasome activation. The NALP3 inflammasome is activated by various microbial and host-derived molecules, including bacterial components, toxins, and DAMPs. These activators induce intracellular K⁺ efflux, which is essential for caspase-1 activation. ATP and nigericin act through a K⁺-dependent mechanism. The study demonstrates that extracellular K⁺ inhibits NALP3 inflammasome activation in human monocytes. Physiological intracellular K⁺ concentrations inhibit inflammasome assembly, suggesting that K⁺ efflux is a common trigger for NALP3 and NALP1 inflammasome activation. The mechanism by which K⁺ efflux induces inflammasome activation is not fully understood, but reactive oxygen species (ROS) may play a role. The data suggest that a decrease in intracellular K⁺ concentration is a common trigger for NALP3 inflammasome activation. This model is supported by the observation that some of the most potent activators of the NALP3 inflammasome are K⁺ channels. The study also highlights the role of K⁺ in the regulation of inflammation and the potential involvement of K⁺ channels in inflammasome activation. The findings suggest that K⁺ efflux is a common and specific trigger for NALP1 and NALP3 inflammasome activation, and that the exact nature and mode of activation of these channels remain to be identified.