The study investigates the role of the calcium-sensing receptor (CASR) in regulating the NLRP3 inflammasome, a key component in the maturation of the proinflammatory cytokine interleukin-1β (IL-1β). The authors found that CASR activation, through increased intracellular calcium (Ca²⁺) and decreased cellular cyclic AMP (cAMP), activates the NLRP3 inflammasome. Specifically, Ca²⁺ or CASR agonists induce Ca²⁺ release from the endoplasmic reticulum, which promotes inflammasome assembly and is essential for spontaneous inflammasome activity in cells from patients with cryopyrin-associated periodic syndromes (CAPS). Additionally, cAMP binds directly to NLRP3, inhibiting inflammasome activation. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is significantly lower than for wild-type NLRP3, and increasing cAMP levels reduces IL-1β production from peripheral blood mononuclear cells of CAPS patients. These findings suggest that Ca²⁺ and cAMP are crucial molecular regulators of the NLRP3 inflammasome, playing critical roles in the pathogenesis of CAPS.The study investigates the role of the calcium-sensing receptor (CASR) in regulating the NLRP3 inflammasome, a key component in the maturation of the proinflammatory cytokine interleukin-1β (IL-1β). The authors found that CASR activation, through increased intracellular calcium (Ca²⁺) and decreased cellular cyclic AMP (cAMP), activates the NLRP3 inflammasome. Specifically, Ca²⁺ or CASR agonists induce Ca²⁺ release from the endoplasmic reticulum, which promotes inflammasome assembly and is essential for spontaneous inflammasome activity in cells from patients with cryopyrin-associated periodic syndromes (CAPS). Additionally, cAMP binds directly to NLRP3, inhibiting inflammasome activation. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is significantly lower than for wild-type NLRP3, and increasing cAMP levels reduces IL-1β production from peripheral blood mononuclear cells of CAPS patients. These findings suggest that Ca²⁺ and cAMP are crucial molecular regulators of the NLRP3 inflammasome, playing critical roles in the pathogenesis of CAPS.