UBA1 Mutations Drive RIPK1-Mediated Cell Death and Monocyte Dysfunction in VEXAS Syndrome

VEXAS syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in UBA1 gene, disrupting cytoplasmic ubiquitin activating enzyme E1 function in hematopoietic progenitors. The pathogenesis remains poorly understood, particularly how UBA1 mutations perturb myeloid function. Here, we combine a genetically engineered THP1 monocytic model with ex vivo analyses of blood and tissue samples from VEXAS patients to investigate the consequences of the canonical UBA1M41V mutation. We show that UBA1 mutated monocytes exhibit TNFα induced cell death, characterized by RIPK1 phosphorylation, and MLKL- and caspase-8 mediated cell death. This is associated with defective transcriptional induction of NFκB target genes and reduced cFLIP(L) expression in response to TNFα. Monocytes also display blunted cytokine responses to multiple Toll like receptor (TLR) agonists despite preserved TLR expression, linked to an impaired NFκB response. UBA1M41V derived macrophages exhibit an inflammatory transcriptional profile and increased secretion of chemokines that promote monocyte recruitment. We demonstrate that these UBA1M41V macrophages display impaired clearance of apoptotic bodies due to lysosomal dysfunction. Together, these findings reveal a pathogenic axis in VEXAS syndrome linking UBA1 loss of function and defective ubiquitination to RIPK1 mediated inflammatory cell death, impaired antimicrobial signaling, and defective resolution mechanisms. Our study provides novel mechanistic insights into the myeloid dysfunction that drives inflammation and cytopenia in VEXAS and highlights the necroptosis pathways as potential therapeutic targets.