Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

慢性肾脏疾病（CKD /尿毒症）仍然令人烦恼，因为它增加了动脉粥样硬化血栓形成的风险，并且还与标准抗血栓形成/抗血小板治疗的出血并发症相关。尽管定义了吲哚尿毒症溶质与血管壁蛋白[如组织因子（TF）和芳烃受体（AHR）]的关联，但尚未完全理解导致血栓形成和出血风险的具体机制。现在，我们介​​绍了一种吲哚溶质特异性动物模型，该模型重点研究溶质与蛋白质的相互作用，并表明，吲哚溶质以AHR和TF依赖性方式介导了所有CKD阶段的血栓形成表型。我们进一步证明，AHR通过STIP1同源性和包含U-box的蛋白1（STUB1）调节TF。作为泛素连接酶，STUB1通过尿毒症环境中的泛素化与TF动态相互作用并降解TF。STUB1与TF表达呈反比关系，并减少了尿毒症血管中STUB1-TF的相互作用，从而支持了STUB1对TF的调节作用。血管平滑肌细胞中STUB1的遗传或药理操作抑制了血流循环中的血栓形成。与CKD患者的标准抗凝治疗药物肝素相比，STUB1扰动可在不延长出血时间的情况下恢复尿毒症高血栓形成表型。我们的工作完善了血栓形成轴（STUB1是吲哚溶质–AHR-TF轴的介体），并扩展了对驱动CKD中脆弱的血栓形成状态的相互联系的理解。