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Peer-reviewedCC BY 4.0Advanced Science

USP5 Stabilizes TGFBR1 to Drive Vascular Smooth Muscle Cell Senescence and Atherosclerosis

  • Xinhai Cui1
  • Yuanlong Hu2
  • Lin Lin2
  • Lei Zhang3
  • Chao Li1
  • Yunlun Li2
  1. 1College of Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine Jinan China
  2. 2Innovation Research Institute of Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine Jinan China
  3. 3Department of Cardiovascular Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan China
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Abstract

Vascular smooth muscle cell (VSMC) senescence contributes importantly to atherosclerotic plaque progression, yet the upstream mechanisms remain incompletely understood. Here, by integrating single‐cell RNA sequencing analysis with human plaque validation, we found that TGFBR1 is enriched in senescent VSMCs in atherosclerotic lesions and correlates with senescence‐associated markers. In vivo, VSMC‐specific TGFBR1 knockin in Apoe‐deficient mice accelerated plaque development and increased VSMC senescence. Mechanistically, we identified the deubiquitinase USP5 as a previously unrecognized stabilizer of TGFBR1. USP5 directly interacted with TGFBR1 and selectively removed K48‐linked polyubiquitin chains at lysine 213, thereby preventing proteasomal degradation. Stabilized TGFBR1 suppressed the mitochondrial enzyme IDH2, driving a metabolic shift toward glycolysis that sustained apoptosis resistance in senescent VSMCs. Conversely, VSMC‐specific knockdown of USP5 reduced TGFBR1 expression, restored IDH2 expression, attenuated glycolytic remodeling, and mitigated atherosclerosis in vivo. Our findings reveal a USP5‐TGFBR1‐IDH2 axis in which site‐specific deubiquitination at K213 links receptor stability to metabolic remodeling and VSMC senescence, identifying USP5 as a potential therapeutic target for atherosclerosis.

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Cite

BibTeXRIS
BibTeX
@article{cui2026usp5,
  title = {{USP5 Stabilizes TGFBR1 to Drive Vascular Smooth Muscle Cell Senescence and Atherosclerosis}},
  author = {Xinhai Cui and Yuanlong Hu and Lin Lin and Lei Zhang and Chao Li and Yunlun Li},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.76911},
  url = {https://doi.org/10.1002/advs.76911},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - USP5 Stabilizes TGFBR1 to Drive Vascular Smooth Muscle Cell Senescence and Atherosclerosis
AU  - Xinhai Cui
AU  - Yuanlong Hu
AU  - Lin Lin
AU  - Lei Zhang
AU  - Chao Li
AU  - Yunlun Li
PY  - 2026
DA  - 2026/08/05
JO  - Advanced Science
DO  - 10.1002/advs.76911
UR  - https://doi.org/10.1002/advs.76911
AB  - Vascular smooth muscle cell (VSMC) senescence contributes importantly to atherosclerotic plaque progression, yet the upstream mechanisms remain incompletely understood. Here, by integrating single‐cell RNA sequencing analysis with human plaque validation, we found that TGFBR1 is enriched in senescent VSMCs in atherosclerotic lesions and correlates with senescence‐associated markers. In vivo, VSMC‐specific TGFBR1 knockin in Apoe‐deficient mice accelerated plaque development and increased VSMC senescence. Mechanistically, we identified the deubiquitinase USP5 as a previously unrecognized stabilizer of TGFBR1. USP5 directly interacted with TGFBR1 and selectively removed K48‐linked polyubiquitin chains at lysine 213, thereby preventing proteasomal degradation. Stabilized TGFBR1 suppressed the mitochondrial enzyme IDH2, driving a metabolic shift toward glycolysis that sustained apoptosis resistance in senescent VSMCs. Conversely, VSMC‐specific knockdown of USP5 reduced TGFBR1 expression, restored IDH2 expression, attenuated glycolytic remodeling, and mitigated atherosclerosis in vivo. Our findings reveal a USP5‐TGFBR1‐IDH2 axis in which site‐specific deubiquitination at K213 links receptor stability to metabolic remodeling and VSMC senescence, identifying USP5 as a potential therapeutic target for atherosclerosis.
SN  - 2198-3844
ER  -