The study investigates the activation mechanism of the NALP3 inflammasome, a key player in the immune response to microbial and danger-associated molecular patterns (DAMPs). The authors found that activation of the NALP3 inflammasome is blocked by inhibiting K⁺ efflux from cells, suggesting that low intracellular K⁺ concentration is a critical trigger for its activation. This effect was observed in both murine macrophages and human monocytes, but not in the IPAF inflammasome, which is activated by bacterial flagellin. In vitro experiments showed that NALP3 assembly and caspase-1 recruitment occur spontaneously at K⁺ concentrations below 90 mm, but are prevented at higher concentrations. The study also suggests that reactive oxygen species (ROS) play a crucial role in NALP3 activation, as their inhibition blocked caspase-1 activation. The findings provide insights into the common mechanism by which various activators of the NALP3 inflammasome trigger its activation, highlighting the importance of K⁺ efflux and ROS in this process.The study investigates the activation mechanism of the NALP3 inflammasome, a key player in the immune response to microbial and danger-associated molecular patterns (DAMPs). The authors found that activation of the NALP3 inflammasome is blocked by inhibiting K⁺ efflux from cells, suggesting that low intracellular K⁺ concentration is a critical trigger for its activation. This effect was observed in both murine macrophages and human monocytes, but not in the IPAF inflammasome, which is activated by bacterial flagellin. In vitro experiments showed that NALP3 assembly and caspase-1 recruitment occur spontaneously at K⁺ concentrations below 90 mm, but are prevented at higher concentrations. The study also suggests that reactive oxygen species (ROS) play a crucial role in NALP3 activation, as their inhibition blocked caspase-1 activation. The findings provide insights into the common mechanism by which various activators of the NALP3 inflammasome trigger its activation, highlighting the importance of K⁺ efflux and ROS in this process.