Abstract
Acute kidney injury (AKI) remains a leading cause of morbidity and mortality, yet the molecular pathways driving kidney tubule damage in AKI are not fully understood. Here, we report dual-specificity phosphatase 26 (DUSP26) as a critical regulator of kidney tubule injury in AKI. In our study, DUSP26 expression was markedly reduced in kidney biopsies from AKI patients of both sexes and in male murine models of cisplatin nephrotoxic and ischemic AKI. This down-regulation was driven by hypermethylation of the gene promoter of DUSP26 in kidney tubular cells. Loss of DUSP26 exacerbated tubular damage, whereas knock-in of DUSP26 specifically in kidney proximal tubule cells conferred protection. Mechanistically, DUSP26 directly bound to p53 to dephosphorylate it at serine 312, dampening the transcriptional activity of p53 towards cell death genes. Pharmacologic inhibition of DUSP26 sensitized kidneys to AKI, whereas DUSP26 overexpression was protective. Pharmacologic inhibition of DUSP26 also exacerbated ischemia-reperfusion injury in the liver. These findings uncover DUSP26 as a key phosphatase guarding against tissue injury by dephosphorylating p53 at serine 312, and highlight the DUSP26-p53 axis as a promising therapeutic target.
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Data availability
The transcriptomic datasets used in this study are available in the Gene Expression Omnibus (GEO) database under accession codes GSE21374, GSE30718 and GSE43974. The mass spectrometry proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository under dataset identifier PXD070789. The bisulfite sequencing data generated in this study have been deposited in the NCBI BioProject database under accession code PRJNA1365351. All datasets generated or analyzed in this study will be available without access restrictions upon publication. Source data are provided with this paper.
Code availability
No custom code was used in this study. All data analyses were performed using standard packages in R (version 4.4.0) and GraphPad Prism (version 10.0).
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Acknowledgements
This work was supported by the Postdoctoral Fellowship Program and China Postdoctoral Science Foundation (grant no. GZB20250487 to Y.F.), the Scientific Research Project of the Hunan Provincial Health Commission (grant no. 20254762 to Y.F.), the National Natural Science Foundation of China (grant nos. 82222013 and 82470731 to A.C.), the Key Program of the Natural Science Foundation of Hunan Province (grant no. 2025JJ30048 to A.C.), the National Key Clinical Specialty Scientific Research Project of the Second Xiangya Hospital, Central South University (grant no. 02201322 to A.C.), the U.S. Department of Veterans Affairs (grant nos. 1TK6BX005236 and I01BX000319 to Z.D.), and the U.S. National Institutes of Health (grant nos. 5R01DK058831 and 5R01DK087843 to Z.D.).
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Y.F. and Z.D. conceived the project and designed the experiments. Y.F. performed most of the experiments, analyzed the data, and wrote the manuscript. Y.X. and Y.H. contributed to the generation and analysis of the genetically modified mouse models. Y.F. and Y.X. performed bioinformatics analysis and supported statistical interpretation. J.C. and S.D. assisted with histological evaluation and clinical sample acquisition. A.C. and Z.D. supervised the entire project and revised the manuscript. All authors read and approved the final version of the manuscript.
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Fu, Y., Xiang, Y., Han, Y. et al. DUSP26 protects against acute kidney injury by dephosphorylating p53 at serine 312. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69688-3
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DOI: https://doi.org/10.1038/s41467-026-69688-3
