Indoxyl Sulfate Promotes Uremic Arterial and Venous Thrombosis by Stabilizing IDO1 via the E3 Ligase SHFM3
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BACKGROUND: The uremic milieu of chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins, which contribute to thrombosis. Indoxyl sulfate, a bona fide uremic toxin, upregulates indoleamine 2,3-dioxygenase 1 (IDO1), thereby augmenting kynurenine biogenesis. Both toxins activate tissue factor and thrombosis. Despite this pathogenic synergy, the mechanisms of indoxyl sulfate-mediated IDO1 stabilization remain undefined. METHODS: We employed targeted metabolomics, super-resolution microscopy, and gain-and loss-of-function experiments using nanoparticle-mediated gene delivery in mice to modulate SHFM3 expression. This was followed by carotid artery or inferior vena cava thrombosis assays in indoxyl sulfate-fed and adenine-induced CKD models. RESULTS: Among several F-box-containing E3 ligases, split-hand/foot malformation 3 (SHFM3) downregulates IDO1 in endothelial cells. SHFM3 constitutively interacts with IDO1, which is partially disrupted by indoxyl sulfate-induced nuclear sequestration of SHFM3 at concentrations corresponding to early to advanced CKD. SHFM3 interacts with the N-terminus of IDO1, ubiquitinates and destabilizes it. Indoxyl sulfate upregulates IDO1 activity, thereby increasing kynurenine biogenesis in N-terminus- and SHFM3-dependent manners. In an indoxyl sulfate-fed mouse model, endothelial cell-specific SHFM3 knockdown increased IDO1 and tissue factor and accelerated arterial thrombosis, and these effects were reversed by endothelial cell-specific SHFM3 overexpression. CKD mice exhibited 55% higher venous thrombogenicity than controls. Endothelial cell-specific SHFM3 overexpression significantly reversed these effects in control mice and to a lesser extent in CKD mice. Serum indoxyl sulfate levels significantly correlated with the global IDO1 activity and venous clot weights. CONCLUSIONS: SHFM3 functions as an indoxyl sulfate-sensitive potent E3 ligase of IDO1, targeting it for degradation, even with partial interaction with IDO1 in the uremic milieu. This work also described CKD-induced venous thrombosis model and supports the selective rewiring of uremic toxins in post-translational proteostasis, amplifying indoxyl sulfate-mediated arterial and venous thrombosis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Indoxyl Sulfate Promotes Uremic Arterial and Venous Thrombosis by Stabilizing IDO1 via the E3 Ligase SHFM3
- Date Crossref
- 21/08/2026
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Boston Medical Center pays non établi dans la noticeÉtablissement de santé
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Boston University Department of Medicine pays non établi dans la noticeUniversité ou école supérieure
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Beth Israel Deaconess Medical Center Division of Hemostasis and Thrombosis pays non établi dans la noticeÉtablissement de santé
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Massachusetts Institute of Technology Department of Biological Engineering pays non établi dans la noticeUniversité ou école supérieure
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Northwestern University Department of Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Lurie Children's Hospital pays non établi dans la noticeÉtablissement de santé
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VA Boston Healthcare System pays non établi dans la noticeÉtablissement de santé
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Stanley Manne Children’s Research Institute and Genetic Medicine and Nanotechnology Development Center pays non établi dans la noticeStructure de recherche
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Institute of Medical Engineering and Science pays non établi dans la noticeStructure de recherche
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Veterans Affairs Boston Healthcare System pays non établi dans la noticeInstitution
Boston Medical Center, Department of Medicine — Boston University et Division of Hemostasis and Thrombosis — Beth Israel Deaconess Medical Center, avec 7 autres affiliations.
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