VEXAS Study Links UBA1 Genotypes to Inflammation and Identifies Potential RIPK3 Target

A study in Arthritis & Rheumatology examined genotype-specific inflammatory mechanisms in VEXAS syndrome, an X-linked autoinflammatory disorder caused by somatic UBA1 mutations. Researchers conducted longitudinal clinical assessments and whole-blood RNA sequencing in 13 patients, who contributed 79 RNA-sequencing samples. They also analyzed peripheral blood using single-cell RNA sequencing and generated human monocytic cell lines carrying UBA1 p.Met41Val, p.Met41Thr, or p.Met41Leu mutations.

Among genes upregulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70; false discovery rate <0.05) and was upregulated in patient monocytes. Mutant cell lines showed graded ubiquitination defects, greatest with p.Met41Val, followed by p.Met41Thr and p.Met41Leu, without external stimulation. Unfolded protein response activation, pro-inflammatory cytokine production, progressive cell death, and RNASE1 upregulation followed the same pattern. More severe genotypes showed enrichment of inflammatory, interferon, and necroptosis signatures.

RIPK3 inhibition markedly attenuated the reported pathological features in cell models, including RNASE1 upregulation. These findings support further investigation of RNASE1 as a disease-activity marker and RIPK3 as a potential therapeutic target. However, the patient cohort was small, and cell-line responses do not establish treatment efficacy or safety in patients. This report is based on the abstract; full text was unavailable.