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Peer-reviewedCC BY 4.0Frontiers in Cardiovascular Medicine

Formononetin relieves chronic stress-related neointimal hyperplasia in mice by regulating HDAC6

  • Shanqian Li1,2,3,4
  • Wanhua Wu1,2,3
  • Chaozhi Xu5
  • Yue Huang6
  • Guixian Wu1,2,3
  • Hongyu Ding1,2,3
  • Zongyi Zhang7
  • Yulin Zhang8
  • Meimei Zheng9
  • Hongxian Wu10
  • Lina Hu1,2,3
10 affiliations
  1. 1The School of Public Health, Guilin Medical University
  2. 2Key Cultivation Laboratory of Life Cycle Health Care Research
  3. 3Guangxi Key Laboratory of Environmental Exposures and Whole Life Cycle Health
  4. 4Department of Clinical Nutrition, Liuzhou Workers’ Hospital
  5. 5School of Artificial Intelligent Medicine, Guilin Medical University
  6. 6Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University
  7. 7Communicable Disease Control Branch, Qingdao Municipal Center for Disease Control and Prevention
  8. 8Department of Nutrition, Second People’s Hospital of Ya'an City
  9. 9School of Health and Hygiene, Beihai Health and Wellness Vocational College
  10. 10Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases
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Abstract

Introduction: Chronic stress severely impairs physical and mental health and is a critical risk factor for cardiovascular diseases. Formononetin (FMN) has shown promising cardiovascular protective effects, yet its functional role and molecular mechanism in chronic stress-triggered arterial neointimal hyperplasia and concomitant mood disturbances remain poorly elucidated.

Methods: Network pharmacology was used to predict the underlying mechanisms of FMN against cardiovascular disease-depression comorbidity. A dual mouse model recapitulating chronic stress and carotid artery injury was established for in vivo validation. Histological staining, behavioral tests, Western blotting, β -galactosidase staining, and in vitro VSMC assays were performed to assess the effects of FMN and the HDAC6 inhibitor TubA.

Results: Network pharmacology identified 111 overlapping targets, with functional enrichment and molecular docking revealing that FMN primarily regulates inflammation, apoptosis, and autophagy via binding to core hub proteins including HDAC6, Bcl-2, and AKT1. In vivo , chronic stress aggravated arterial intimal hyperplasia and aortic senescence, and induced anxiety- and depression-like behaviors. FMN treatment notably improved emotional disorders, reduced HDAC6 expression, activated autophagy (increased LC3B/A ratio), inhibited apoptosis (elevated Bcl-2/Bax ratio), attenuated NLRP3 and IL-6 expression, and alleviated intimal thickening. The HDAC6 inhibitor TubA recapitulated the vascular protective effects of FMN.

Discussion: FMN attenuates chronic stress-induced vascular injury and emotional dysfunction via suppressing HDAC6 signaling to restore autophagy, inhibit inflammation, and reduce apoptosis. This study unveils the dual cardio-neuroprotective capacities of FMN and provides novel mechanistic insights for the treatment of chronic stress-related cardiocerebral comorbidities.

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Cite

BibTeXRIS
BibTeX
@article{li2026formononetin,
  title = {{Formononetin relieves chronic stress-related neointimal hyperplasia in mice by regulating HDAC6}},
  author = {Shanqian Li and Wanhua Wu and Chaozhi Xu and Yue Huang and Guixian Wu and Hongyu Ding and Zongyi Zhang and Yulin Zhang and Meimei Zheng and Hongxian Wu and Lina Hu},
  journal = {Frontiers in Cardiovascular Medicine},
  year = {2026},
  month = oct,
  doi = {10.3389/fcvm.2026.1865656},
  url = {https://www.frontiersin.org/articles/10.3389/fcvm.2026.1865656/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Formononetin relieves chronic stress-related neointimal hyperplasia in mice by regulating HDAC6
AU  - Shanqian Li
AU  - Wanhua Wu
AU  - Chaozhi Xu
AU  - Yue Huang
AU  - Guixian Wu
AU  - Hongyu Ding
AU  - Zongyi Zhang
AU  - Yulin Zhang
AU  - Meimei Zheng
AU  - Hongxian Wu
AU  - Lina Hu
PY  - 2026
DA  - 2026/10/07
JO  - Frontiers in Cardiovascular Medicine
DO  - 10.3389/fcvm.2026.1865656
UR  - https://www.frontiersin.org/articles/10.3389/fcvm.2026.1865656/full
AB  - Introduction: Chronic stress severely impairs physical and mental health and is a critical risk factor for cardiovascular diseases. Formononetin (FMN) has shown promising cardiovascular protective effects, yet its functional role and molecular mechanism in chronic stress-triggered arterial neointimal hyperplasia and concomitant mood disturbances remain poorly elucidated.  Methods: Network pharmacology was used to predict the underlying mechanisms of FMN against cardiovascular disease-depression comorbidity. A dual mouse model recapitulating chronic stress and carotid artery injury was established for in vivo validation. Histological staining, behavioral tests, Western blotting, β -galactosidase staining, and in vitro VSMC assays were performed to assess the effects of FMN and the HDAC6 inhibitor TubA.  Results: Network pharmacology identified 111 overlapping targets, with functional enrichment and molecular docking revealing that FMN primarily regulates inflammation, apoptosis, and autophagy via binding to core hub proteins including HDAC6, Bcl-2, and AKT1. In vivo , chronic stress aggravated arterial intimal hyperplasia and aortic senescence, and induced anxiety- and depression-like behaviors. FMN treatment notably improved emotional disorders, reduced HDAC6 expression, activated autophagy (increased LC3B/A ratio), inhibited apoptosis (elevated Bcl-2/Bax ratio), attenuated NLRP3 and IL-6 expression, and alleviated intimal thickening. The HDAC6 inhibitor TubA recapitulated the vascular protective effects of FMN.  Discussion: FMN attenuates chronic stress-induced vascular injury and emotional dysfunction via suppressing HDAC6 signaling to restore autophagy, inhibit inflammation, and reduce apoptosis. This study unveils the dual cardio-neuroprotective capacities of FMN and provides novel mechanistic insights for the treatment of chronic stress-related cardiocerebral comorbidities.
SN  - 2297-055X
ER  -