Targeting Nupr1-Mediated p53 Mitochondrial Sequestration Alleviates Aortic Dissection by Restoring the Gadd45b-Dependent Survival Program.
6 affiliations
- 1Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
- 2Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, China.
- 3Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, China.
- 4Department of Anesthesiology, Union Hospital, Fujian Medical University, Fuzhou, China.
- 5The School of Pharmacy, Fujian Medical University, Fuzhou, China.
- 6Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, China.
Abstract
Aortic dissection (AD) is a catastrophic cardiovascular emergency triggered by severe pathological stress. While continuous stress drives vascular smooth muscle cell (VSMC) apoptosis via mitochondrial dysfunction, the precise upstream orchestrators linking these stress signals to the mitochondrial apoptotic cascade remain elusive. By integrating clinical observations and single-cell RNA sequencing, we found that Nuclear Protein 1 (Nupr1), a critical stress-responsive factor, is significantly upregulated in aortas from AD patients and murine models, with enrichment in VSMCs. Remarkably, VSMC-specific Nupr1 deficiency significantly ameliorated AD progression in vivo. Mechanistically, Nupr1 undergoes massive mitochondrial accumulation in Ang II-induced apoptotic VSMCs. Rather than operating as a conventional transcriptional regulator, mitochondrially enriched Nupr1 functions as a pathological spatial switch. It sequesters p53 within mitochondria, driving transcription-independent apoptosis while simultaneously blunting the protective Gadd45b-mediated survival program. Furthermore, in vivo Gadd45b overexpression was sufficient to rescue mitochondrial dysfunction and ameliorate vascular collapse. Taken together, our findings conceptualize the Nupr1-p53-Gadd45b axis as an important determinant of VSMC fate and provide a novel and promising therapeutic strategy for preventing AD progression.
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BibTeX
@article{yang2026targeting,
title = {{Targeting Nupr1-Mediated p53 Mitochondrial Sequestration Alleviates Aortic Dissection by Restoring the Gadd45b-Dependent Survival Program.}},
author = {Xi Yang and Ke-Yuan Chen and Yue Tian and Zong-Sheng Jiang and Jian Lei and Xing-Hui Zhuang and Jiang-Bin Wu and Le-Le Tang and Hao-Yu Li and Xiao-Hui Chen and Yue Wang and Yu-Mei Li and Zhi-Huang Qiu and Zi-Wen Cai and Liang-Wan Chen},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78143},
url = {https://europepmc.org/article/MED/42881547},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting Nupr1-Mediated p53 Mitochondrial Sequestration Alleviates Aortic Dissection by Restoring the Gadd45b-Dependent Survival Program.
AU - Xi Yang
AU - Ke-Yuan Chen
AU - Yue Tian
AU - Zong-Sheng Jiang
AU - Jian Lei
AU - Xing-Hui Zhuang
AU - Jiang-Bin Wu
AU - Le-Le Tang
AU - Hao-Yu Li
AU - Xiao-Hui Chen
AU - Yue Wang
AU - Yu-Mei Li
AU - Zhi-Huang Qiu
AU - Zi-Wen Cai
AU - Liang-Wan Chen
PY - 2026
DA - 2026/10/15
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78143
UR - https://europepmc.org/article/MED/42881547
AB - Aortic dissection (AD) is a catastrophic cardiovascular emergency triggered by severe pathological stress. While continuous stress drives vascular smooth muscle cell (VSMC) apoptosis via mitochondrial dysfunction, the precise upstream orchestrators linking these stress signals to the mitochondrial apoptotic cascade remain elusive. By integrating clinical observations and single-cell RNA sequencing, we found that Nuclear Protein 1 (Nupr1), a critical stress-responsive factor, is significantly upregulated in aortas from AD patients and murine models, with enrichment in VSMCs. Remarkably, VSMC-specific Nupr1 deficiency significantly ameliorated AD progression in vivo. Mechanistically, Nupr1 undergoes massive mitochondrial accumulation in Ang II-induced apoptotic VSMCs. Rather than operating as a conventional transcriptional regulator, mitochondrially enriched Nupr1 functions as a pathological spatial switch. It sequesters p53 within mitochondria, driving transcription-independent apoptosis while simultaneously blunting the protective Gadd45b-mediated survival program. Furthermore, in vivo Gadd45b overexpression was sufficient to rescue mitochondrial dysfunction and ameliorate vascular collapse. Taken together, our findings conceptualize the Nupr1-p53-Gadd45b axis as an important determinant of VSMC fate and provide a novel and promising therapeutic strategy for preventing AD progression.
SN - 2198-3844
ER -