Abstract: SA-PO0171
DUSP26 Protects Against AKI by Dephosphorylating p53 at Serine 312
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Fu, Ying, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
- Duan, Shaobin, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
- Chen, Anqun, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
- Dong, Zheng, Augusta University, Augusta, Georgia, United States
Background
Acute kidney injury (AKI) is a serious condition linked to high morbidity and progression to chronic kidney disease. Tubular epithelial apoptosis is central to AKI, yet its upstream regulation remains unclear. While kinase signaling is well characterized, phosphatase-mediated control is underexplored. DUSP26, a non-classical phosphatase implicated in cancer and metabolic disorders, has not been studied in kidney injury. We identified DUSP26 as a stress-inducible phosphatase that modulates tubular injury by regulating p53 activity.
Methods
Transcriptomic analysis of human AKI datasets, combined with LASSO and SVM-RFE, identified DUSP26 as a downregulated gene. Its expression was validated in patient biopsies and murine models of cisplatin- and ischemia-induced AKI. Functional studies included methylation analysis, gain/loss-of-function in tubular cells, and proximal tubule-specific knock-in mice. Co-IP and phosphoproteomics were used to characterize DUSP26-p53 interactions.
Results
DUSP26 downregulation in AKI was due to promoter hypermethylation. Loss of DUSP26, genetically or pharmacologically, aggravated tubular apoptosis and renal dysfunction. DUSP26 overexpression or knock-in conferred protection. Mechanistically, DUSP26 bound to p53 and dephosphorylated serine 312, a key site for p53 stabilization and pro-apoptotic transcription. In p53-deficient cells, S312A-mutant p53 reduced apoptosis and target gene expression compared to wild-type p53. Knock-in mice showed reduced p-p53-S312, less apoptosis, and improved renal outcomes. The same axis mitigated liver injury in hepatic ischemia.
Conclusion
DUSP26 dephosphorylates p53 at Ser312 to suppress tubular apoptosis and protect against AKI. The DUSP26–p53S312 axis offers a novel and actionable therapeutic target for acute organ injury.
Funding
- Other NIH Support