VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation. Somatic mutations in the UBA1 gene cause severe adult-onset auto-inflammatory disease, leading to monocyte dysfunction and increased proinflammatory cytokines such as IL-1β and IL-18. These findings suggest that inflammasome activation and inflammatory cell death are key features of VEXAS. Monocytes from VEXAS patients show reduced numbers and dysfunctional characteristics, with aberrant expression of chemokine receptors. Skin biopsies reveal increased inflammatory cells, including CD16⁺CD163⁺ monocytes and M1 macrophages. Transcriptomic analysis shows enrichment of TNF-α and NFκB signaling pathways, which may mediate cell death and inflammation. Single-cell RNA sequencing highlights dysregulated proinflammatory and cell death signatures in monocytes. The study also identifies increased apoptosis, pyroptosis, and necroptosis in VEXAS patients. These findings suggest that targeting inflammasome activation and inflammatory cell death could be therapeutic strategies for VEXAS. The study highlights the importance of understanding the molecular mechanisms underlying monocyte dysfunction and inflammatory responses in VEXAS.VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation. Somatic mutations in the UBA1 gene cause severe adult-onset auto-inflammatory disease, leading to monocyte dysfunction and increased proinflammatory cytokines such as IL-1β and IL-18. These findings suggest that inflammasome activation and inflammatory cell death are key features of VEXAS. Monocytes from VEXAS patients show reduced numbers and dysfunctional characteristics, with aberrant expression of chemokine receptors. Skin biopsies reveal increased inflammatory cells, including CD16⁺CD163⁺ monocytes and M1 macrophages. Transcriptomic analysis shows enrichment of TNF-α and NFκB signaling pathways, which may mediate cell death and inflammation. Single-cell RNA sequencing highlights dysregulated proinflammatory and cell death signatures in monocytes. The study also identifies increased apoptosis, pyroptosis, and necroptosis in VEXAS patients. These findings suggest that targeting inflammasome activation and inflammatory cell death could be therapeutic strategies for VEXAS. The study highlights the importance of understanding the molecular mechanisms underlying monocyte dysfunction and inflammatory responses in VEXAS.