VEXAS syndrome, characterized by severe adult-onset auto-inflammatory disease, is associated with mutations in the *UBAI* gene. This study investigates the physiological and clinical impact of these mutations in a unique cohort of VEXAS patients. Monocytes from VEXAS patients exhibit quantitative and qualitative impairments, showing features of exhaustion and aberrant expression of chemokine receptors. Peripheral blood from VEXAS patients shows increased levels of proinflammatory cytokines, including IL-1β and IL-18, reflecting inflammasome activation and myeloid cell dysregulation. Gene expression analysis confirms these findings and reveals significant enrichment of TNF-α and NFκB signaling pathways, which mediate cell death and inflammation. The study suggests that controlling inflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome. The prevalence of VEXAS syndrome is not yet known, but it is likely underestimated. The disease primarily affects males and is associated with fever, neutrophilic cutaneous lesions, arthralgias, pulmonary inflammation, chondritis, and vasculitis. Hematologic manifestations, such as macrocytic anemia, thrombocytopenia, thromboembolic disease, and progressive bone marrow failure, are also common. Conventional treatments are often ineffective, but biological targeted therapies and hypomethylating agents like azacytidine show partial efficacy. Allogeneic stem cell transplantation is the only curative option for severe cases. The study highlights the importance of targeting inflammasome activation and inflammatory cell death pathways in the treatment of VEXAS syndrome.VEXAS syndrome, characterized by severe adult-onset auto-inflammatory disease, is associated with mutations in the *UBAI* gene. This study investigates the physiological and clinical impact of these mutations in a unique cohort of VEXAS patients. Monocytes from VEXAS patients exhibit quantitative and qualitative impairments, showing features of exhaustion and aberrant expression of chemokine receptors. Peripheral blood from VEXAS patients shows increased levels of proinflammatory cytokines, including IL-1β and IL-18, reflecting inflammasome activation and myeloid cell dysregulation. Gene expression analysis confirms these findings and reveals significant enrichment of TNF-α and NFκB signaling pathways, which mediate cell death and inflammation. The study suggests that controlling inflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome. The prevalence of VEXAS syndrome is not yet known, but it is likely underestimated. The disease primarily affects males and is associated with fever, neutrophilic cutaneous lesions, arthralgias, pulmonary inflammation, chondritis, and vasculitis. Hematologic manifestations, such as macrocytic anemia, thrombocytopenia, thromboembolic disease, and progressive bone marrow failure, are also common. Conventional treatments are often ineffective, but biological targeted therapies and hypomethylating agents like azacytidine show partial efficacy. Allogeneic stem cell transplantation is the only curative option for severe cases. The study highlights the importance of targeting inflammasome activation and inflammatory cell death pathways in the treatment of VEXAS syndrome.