Ubiquitin-specific peptidase 10 promotes renal interstitial fibrosis progression through deubiquitinating and stabilizing P53 protein

Suwen Liu; Yunwen Yang; Qian Li; Lichun Yu; Zihan Zong; Ruixian Zang; Wentao Ji; Shuzhen Sun

doi:10.1016/j.bbadis.2025.167660

Ubiquitin-specific peptidase 10 promotes renal interstitial fibrosis progression through deubiquitinating and stabilizing P53 protein

Biochim Biophys Acta Mol Basis Dis. 2025 Jan 7;1871(3):167660. doi: 10.1016/j.bbadis.2025.167660. Online ahead of print.

Authors

Suwen Liu¹, Yunwen Yang², Qian Li³, Lichun Yu³, Zihan Zong⁴, Ruixian Zang⁴, Wentao Ji⁴, Shuzhen Sun⁵

Affiliations

¹ Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China. Electronic address: [email protected].
² Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
³ Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
⁴ Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
⁵ Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China. Electronic address: [email protected].

PMID: 39788218
DOI: 10.1016/j.bbadis.2025.167660

Abstract

Renal interstitial fibrosis is the main factor determining chronic kidney disease (CKD) progression, and renal tubular epithelial cells are the key drivers of this pathological process. Herein, we revealed significantly increased ubiquitin-specific peptidase 10 (USP10) expression in the kidney tissues of both patients with CKD and mice induced by unilateral ureteral obstruction, as well as in transforming growth factor-beta 1 (TGFβ1)-induced renal tubular epithelial cells. In vivo, treatment with the USP10 small molecule inhibitor Spautin-1, which inhibits its deubiquitinating activity, weakened renal interstitial fibrosis progression and alleviated the subsequent inflammatory response and oxidative stress in male mice. In vitro, knocking down USP10 or inhibiting its deubiquitinating activity through Spautin-1 significantly reduced fibronectin expression and ameliorated TGFβ1-induced renal tubular epithelial cell dedifferentiation. Additionally, our results revealed that USP10 directly binds to P53 and removes the K48-linked polyubiquitin chains from P53, thereby affecting its ubiquitination, stability, and nuclear translocation, which subsequently leads to the upregulation of P21 and promotes fibrotic gene expression in injured renal tubular epithelial cells, ultimately exacerbating renal interstitial fibrosis. In conclusion, USP10 is inhibited through the P53 signaling pathway to alleviate the progression of renal interstitial fibrosis and serve as a potential target for treating CKD.

Keywords: CKD; Deubiquitination; P53; Renal interstitial fibrosis; USP10.