2025年11月3日出版的《自然》杂志发表了美国纪念斯隆-凯特琳癌症中心Alexander D. Gitlin团队的最新成果，他们开发出VEXAS综合征炎症和髓系偏倚的独立机制。

小组使用体细胞基因编辑方法来模拟原代巨噬细胞和HSPCs中与VEXAS相关的UBA1突变。暴露于炎症刺激下的UBA1突变体巨噬细胞分别发生由Caspase-8和RIPK3-MLKL介导的异常凋亡和坏死细胞死亡。因此，在TNF或LPS刺激的小鼠中，UBA1抑制剂TAK-243以RIPK3-Caspase-8依赖的方式加重炎症。相比之下，HSPCs中的Uba1突变诱导了不依赖于RIPK3-Caspase-8的未折叠蛋白反应和髓系偏倚。在机制上，UBA1突变体巨噬细胞的异常细胞死亡与Lys63/Met1（即线性）炎症信号复合物多泛素化的动力学缺陷相吻合。总的来说，他们的结果将VEXAS的发病机制与罕见的单基因自身炎症综合征联系起来；突出在泛素化级联中的顶端突变引起的特定泛素相关缺陷；并支持对炎性细胞死亡轴的靶向治疗。

据介绍，造血干细胞和祖细胞（HSPCs）中E1泛素激活酶UBA1的体细胞获得性突变最近被确定为成人发病的自身炎症综合征VEXAS（空泡，E1酶，X连锁，自身炎症，体细胞）的主因。在VEXAS中，UBA1突变导致HSPC和髓细胞室（而不是淋巴细胞室）内的克隆扩增。尽管其严重性和普遍性，UBA1突变介导多器官自身炎症和血液病的机制尚不清楚。

附：英文原文

Title: Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome

Author: Narendra, Varun K., Das, Tandrila, Wierciszewski, Linsey J., Londoner, Rebecca J., Morrison, Joshua K., Martindale, Pia, Devine, Tessa, Chen, Kevin, Trombetta, Michael, Kanno, Yuzuka, Casiano, Alejandro E., de Stanchina, Elisa, Lareau, Caleb A., Lowe, Scott W., Gitlin, Alexander D.

Issue&Volume: 2025-11-03

Abstract: Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. UBA1 mutations in VEXAS lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and hematologic disease are unknown. Here, we employ somatic gene editing approaches to model VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 and RIPK3-MLKL, respectively. Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-Caspase-8-dependent manner. In contrast, Uba1 mutation in HSPCs induced an unfolded protein response and myeloid bias independently of RIPK3-Caspase-8. Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kinetic defect in Lys63/Met1 (i.e., linear) polyubiquitylation of inflammatory signaling complexes. Collectively, our results link VEXAS pathogenesis with that of rarer monogenic autoinflammatory syndromes; highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade; and support therapeutic targeting of the inflammatory cell death axis in VEXAS.

DOI: 10.1038/s41586-025-09815-0

Source: https://www.nature.com/articles/s41586-025-09815-0