A Novel Peptide Targeting the USP25-SIRT1 Interaction Activates SIRT1 to Suppress Cell Senescence.
8 affiliations
- 1State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
- 2Sanming Hospital of Integrated Medicine, Sanming, China.
- 3Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China.
- 4Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital School of Medicine Tongji University, Shanghai, China.
- 5State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- 6Cancer Center, Tongji University School of Medicine, Shanghai, China.
- 7Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
- 8Affiliated Shanghai Blue Cross Brain Hospital, School of Medicine, Tongji University, Shanghai, China.
Abstract
The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function. Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence. Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.
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BibTeX
@article{zhou2026novel,
title = {{A Novel Peptide Targeting the USP25-SIRT1 Interaction Activates SIRT1 to Suppress Cell Senescence.}},
author = {YuJuan Zhou and Xinshu Wang and Jiyuan Zhang and Hanqiong Qiang and Xinru Zhao and Jingyi Luo and Yanjun Ji and Jiakai Yao and Linhui Zhai and Tingting Zhang and Ke Li and Yuping Chen and Jian Yuan and Lei Li and Yunhui Li},
journal = {Aging cell},
year = {2026},
month = oct,
doi = {10.1111/acel.70786},
url = {https://europepmc.org/article/MED/42963318},
note = {CC BY},
}
RIS
TY - JOUR
TI - A Novel Peptide Targeting the USP25-SIRT1 Interaction Activates SIRT1 to Suppress Cell Senescence.
AU - YuJuan Zhou
AU - Xinshu Wang
AU - Jiyuan Zhang
AU - Hanqiong Qiang
AU - Xinru Zhao
AU - Jingyi Luo
AU - Yanjun Ji
AU - Jiakai Yao
AU - Linhui Zhai
AU - Tingting Zhang
AU - Ke Li
AU - Yuping Chen
AU - Jian Yuan
AU - Lei Li
AU - Yunhui Li
PY - 2026
DA - 2026/10/30
JO - Aging cell
DO - 10.1111/acel.70786
UR - https://europepmc.org/article/MED/42963318
AB - The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function. Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence. Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.
SN - 1474-9718
SN - 1474-9726
ER -