2. Academic Validation
  3. TET3 is a regulator and can be targeted for the intervention of myocardial fibrosis

TET3 is a regulator and can be targeted for the intervention of myocardial fibrosis

  • EMBO Mol Med. 2025 Oct;17(10):2809-2826. doi: 10.1038/s44321-025-00305-4.
Chenghao Zhu # 1,  Wenxuan Hong # 2,  Yuwen Zhu # 3,  Yujia Xue 1,  Zemin Fang 4,  Dingsheng Jiang 5,  Yong Xu 6,  Ming Kong 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
  • 2 Department of Cardiology, Affiliated Hospital of Jiangnan University, Wuxi, China.
  • 3 Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
  • 4 Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. jds@hust.edu.cn.
  • 6 Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. yjxu@njmu.edu.cn.
  • 7 State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China. mingkong@cpu.edu.cn.
  • 8 Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. mingkong@cpu.edu.cn.
  • # Contributed equally.
PMID: 40921878 DOI: 10.1038/s44321-025-00305-4
Abstract

Cardiac fibrosis contributes to adverse cardiac remodeling and loss of heart function eventually leading to heart failure (HF). Resident cardiac fibroblasts are the principal source of myofibroblasts that produce extracellular matrix proteins to mediate cardiac fibrosis. We report that TET3 depletion in cultured cardiac fibroblasts blocked transition to myofibroblasts in response to different pro-fibrogenic stimuli. Consistently, deletion of TET3 from quiescent or activated fibroblast (myofibroblast) attenuated cardiac fibrosis and rescued heart function in mice. Importantly, a small-molecule TET3-specific degrader Bobcat339 displayed therapeutic potential by mitigating cardiac fibrosis and normalizing heart function when administered post-surgery. Integrated transcriptomic analysis identified the mechanosensor Piezo2 as a downstream target for TET3. Piezo2 inhibition dampened fibroblast activation in vitro and ameliorated cardiac fibrosis in vivo. Mechanistically, Piezo2 promoted fibroblast activation by modulating the activities of mechanosensitive transcription factors. Finally, relevance of TET3 and Piezo2 was verified in heart specimens collected from HF patients. In conclusion, our data demonstrate that TET3 is a pivotal regulator of cardiac fibrosis and can be potentially targeted for the intervention of heart failure.

Keywords

Cardiac Fibrosis; Epigenetics; Fibroblast; Heart Failure; Myofibroblast.

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