The NLRP3 inflammasome is a key component of the innate immune system that activates caspase-1 and promotes the secretion of pro-inflammatory cytokines IL-1β and IL-18 in response to microbial infection and cellular damage. However, its aberrant activation is linked to various inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer's disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, including ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS), and lysosomal damage. The activation process involves two signals: a priming signal that upregulates NLRP3 and pro-IL-1β, and an activation signal that triggers the inflammasome assembly. Post-translational modifications and interacting partners of NLRP3 regulate its activation. The NLRP3 inflammasome is critical for host defense against infections but can also contribute to disease when dysregulated. Recent studies have identified Nek7 as a critical regulator of NLRP3 inflammasome activation, as well as the role of newly synthesized mitochondrial DNA in its activation. Understanding the mechanisms of NLRP3 inflammasome activation and regulation is essential for developing therapeutic strategies for inflammatory diseases.The NLRP3 inflammasome is a key component of the innate immune system that activates caspase-1 and promotes the secretion of pro-inflammatory cytokines IL-1β and IL-18 in response to microbial infection and cellular damage. However, its aberrant activation is linked to various inflammatory disorders, including cryopyrin-associated periodic syndromes, Alzheimer's disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, including ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS), and lysosomal damage. The activation process involves two signals: a priming signal that upregulates NLRP3 and pro-IL-1β, and an activation signal that triggers the inflammasome assembly. Post-translational modifications and interacting partners of NLRP3 regulate its activation. The NLRP3 inflammasome is critical for host defense against infections but can also contribute to disease when dysregulated. Recent studies have identified Nek7 as a critical regulator of NLRP3 inflammasome activation, as well as the role of newly synthesized mitochondrial DNA in its activation. Understanding the mechanisms of NLRP3 inflammasome activation and regulation is essential for developing therapeutic strategies for inflammatory diseases.