ArticleMolecular medicine (Cambridge, Mass.)2025
Ubiquitin-specific protease 38 modulates atrial fibrillation susceptibility in chronic kidney disease via STRAP stabilization and activation of TGF-β/SMAD signaling.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Deubiquitinases as Regulators and Therapeutic Targets in Vascular Diseases.International journal of molecular sciences · 2026Review
- MATR3 regulates METTL3-Mediated mJournal of bioenergetics and biomembranes · 2026Article
- The Ubiquitin-Specific Protease Family: Master Regulators of Renal Fibrosis Pathogenesis and Therapeutic Targets.International journal of molecular sciences · 2026Review
- The role of ubiquitination in the pathogenesis of atrial fibrillation: mechanisms and therapeutic implications.Frontiers in pharmacology · 2026Review
- Comprehensive analysis of the TGF-β signaling pathway: molecular mechanisms, disease drivers, and frontiers in clinical translation.Frontiers in immunology · 2026Review
- Targeting the Ubiquitin-Proteasome System in Atrial Fibrillation: Mechanistic Insights and Translational Perspectives.Current issues in molecular biology · 2025Review
- Enzymatic post-translational modifications of proteins in chronic kidney disease: mechanisms, regulation, and clinical significance.Frontiers in pharmacology · 2025Review
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Authors and funding
7 authors.
Funding
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Abstract
objectiveThis study aimed to elucidate the role of the deubiquitinase USP38 in chronic kidney disease (CKD)-associated atrial fibrillation (AF) by investigating its impact on atrial structural and electrical remodeling and its interaction with STRAP and TGF-β/SMAD signaling.
methodsA murine CKD model was established using a two-stage 5/6 nephrectomy. Cardiomyocyte-specific USP38 knockout (USP38-CKO) and overexpression (USP38-TG) mice were generated. Atrial remodeling, electrophysiological parameters, and fibrosis markers were assessed by echocardiography, histology, and immunoblotting. In parallel, HL-1 cells were treated with indoxyl sulfate (100 μM) and subjected to adenoviral-mediated USP38 modulation. Molecular interactions between USP38 and STRAP were evaluated using immunofluorescence, co-immunoprecipitation, and ubiquitination assays. STRAP knockdown studies further validated the downstream effects of USP38.
resultsCKD induced significant upregulation of USP38 in atrial tissue and HL-1 cells. USP38-CKO attenuated atrial fibrosis and reduced collagen I/III and α-SMA expression, whereas USP38-TG exacerbated these effects. Notably, USP38 modulation did not significantly alter atrial effective refractory period, suggesting its primary involvement in structural rather than direct electrical remodeling. Mechanistic studies revealed that USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling. STRAP knockdown reversed the pro-fibrotic and arrhythmogenic effects induced by USP38 overexpression.
conclusionUSP38 is a critical mediator of CKD-associated AF, promoting atrial fibrosis and electrical remodeling via STRAP stabilization and TGF-β/SMAD pathway activation. Targeting USP38 may represent a novel therapeutic strategy for CKD-associated AF.
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