ArticleActa pharmacologica Sinica2025
USP11 promotes renal tubular cell pyroptosis and fibrosis in UUO mice via inhibiting KLF4 ubiquitin degradation.
Article in Acta pharmacologica Sinica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Ubiquitin-specific protease 11 facilitates the activation and proliferation of renal interstitial fibroblasts through epidermal growth factor receptor signaling pathways.Renal failure · 2026Article
- Deubiquitinating enzymes in kidney diseases: Molecular mechanisms, pathological roles and therapeutic opportunities (Review).Molecular medicine reports · 2026Review
- Rosiglitazone alleviates white matter injury by inhibiting NLRP3/capspase-1 mediated microglial pyroptosis via downregulating KLF4.Experimental brain research · 2026Article
- Article
- Gastrodin as a nephroprotective agent: Molecular docking-based modulation of oxidative stress, fibrosis, and inflammation.Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences · 2026Review
- Regulated cell death: a multidimensional regulatory network in the pathogenesis of renal fibrosis.Apoptosis : an international journal on programmed cell death · 2026Review
- The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma.Cell biology and toxicology · 2026Review
- Targeting pyroptosis in renal fibrosis: From molecular mechanisms to therapeutic horizons (Review).International journal of molecular medicine · 2026Review
- Phillygenin, a Plant-Derived Lignan, Attenuates Renal Inflammation, Fibrosis, and Pyroptosis in a Unilateral Ureteral Obstruction Model.Nutrients · 2026Article
- Renal fibrosis is induced by hyperactive Wnt/β-catenin pathway via microbial-mediated tryptophan metabolism-driven AhR signaling in rodents and humans.Cellular and molecular life sciences : CMLS · 2026Article
- Review
- The Ubiquitin-Specific Protease Family: Master Regulators of Renal Fibrosis Pathogenesis and Therapeutic Targets.International journal of molecular sciences · 2026Review
- Functional role of deubiquitinating enzyme USP39 in inhibiting pyroptosis in human acute myeloid leukemia.Journal of molecular histology · 2026Article
- Nanomedicine-Driven Precision Therapy for Renal Fibrosis: From Mechanistic Insights to Kidney-Targeted Interventions.International journal of nanomedicine · 2026Review
- TRPC6 Inhibition Attenuates Renal Tubulointerstitial Fibrosis via the Reactive Oxygen Species/TXNIP/NLRP3 Signaling Pathway.Kidney & blood pressure research · 2026Article
- Enzymatic post-translational modifications of proteins in chronic kidney disease: mechanisms, regulation, and clinical significance.Frontiers in pharmacology · 2025Review
- Tissue-resident macrophages and renal diseases: landscapes and treatment directions.Frontiers in immunology · 2025Review
- KLF4: a multifunctional nexus connecting tumor progression and immune regulation.Frontiers in immunology · 2025Review
- Gasdermin D regulates the activation of EGFR in colorectal cancer.Journal of translational medicine · 2024Article
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18 authors.
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Abstract
The pyroptosis of renal tubular epithelial cells leads to tubular loss and inflammation and then promotes renal fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) can bidirectionally regulate the transcription of target genes. Our previous study revealed that sustained elevation of KLF4 is responsible for the transition of acute kidney injury (AKI) into chronic kidney disease (CKD) and renal fibrosis. In this study, we explored the upstream mechanisms of renal tubular epithelial cell pyroptosis from the perspective of posttranslational regulation and focused on the transcription factor KLF4. Mice were subjected to unilateral ureteral obstruction (UUO) surgery and euthanized on D7 or D14 for renal tissue harvesting. We showed that the pyroptosis of renal tubular epithelial cells mediated by both the Caspase-1/GSDMD and Caspase-3/GSDME pathways was time-dependently increased in UUO mouse kidneys. Furthermore, we found that the expression of the transcription factor KLF4 was also upregulated in a time-dependent manner in UUO mouse kidneys. Tubular epithelial cell-specific Klf4 knockout alleviated UUO-induced pyroptosis and renal fibrosis. In Ang II-treated mouse renal proximal tubular epithelial cells (MTECs), we demonstrated that KLF4 bound to the promoter regions of Caspase-3 and Caspase-1 and directly increased their transcription. In addition, we found that ubiquitin-specific protease 11 (USP11) was increased in UUO mouse kidneys. USP11 deubiquitinated KLF4. Knockout of Usp11 or pretreatment with the USP11 inhibitor mitoxantrone (3 mg/kg, i.p., twice a week for two weeks before UUO surgery) significantly alleviated the increases in KLF4 expression, pyroptosis and renal fibrosis. These results demonstrated that the increased expression of USP11 in renal tubular cells prevents the ubiquitin degradation of KLF4 and that elevated KLF4 promotes inflammation and renal fibrosis by initiating tubular cell pyroptosis.
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