This study examined genotype-specific inflammatory mechanisms in VEXAS syndrome (caused by somatic UBA1 mutations) using longitudinal whole-blood and single-cell RNA-seq from 13 patients (79 samples) and human monocytic cell lines engineered to carry each major UBA1 variant (p.Met41Val, p.Met41Thr, p.Met41Leu).
RNASE1 was the strongest correlate of longitudinal disease activity (r = 0.70, FDR < 0.05) and was elevated in patient monocytes. Ubiquitination defects, unfolded protein response, pro-inflammatory cytokine production, cell death, and RNASE1 upregulation followed a graded severity pattern (p.Met41Val > p.Met41Thr > p.Met41Leu). RIPK3 inhibition markedly attenuated all these pathological features across genotypes.
Small patient cohort (n = 13), limiting statistical power and generalizability. Cell-line models may not fully replicate primary patient hematopoietic cell biology. Findings are preclinical; no RIPK3 inhibitor has been tested in VEXAS patients.
RNASE1 may serve as a genotype-sensitive biomarker of VEXAS disease activity worth tracking longitudinally. RIPK3 inhibition is a promising precision therapeutic target in VEXAS, particularly for severe UBA1 genotypes, but requires clinical validation.
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