journal article·2025-03Open access

Cardiomyocyte Foxp1‐Specific Deletion Promotes Post‐injury Heart Regeneration via Targeting Usp20‐HIF1ɑ‐Hand1 Signaling Pathway

Yanfang Wang, Xiaoyu Wang, Ji Fang, Xiaoli Chen, Teng Xu, Tao Zhuang, Sheng Peng, Wenzhen Bao, Wenrun Wu, Yushi Lu, Haikun Wang, Brian Tomlinson, Paul Chan, Shougang Zhuang, Qi Zhang, Lin Zhang, Zhongmin Liu, Jingjiang Pi, Yuzhen Zhang, Jie Liu

Advanced Science· Volume 12· Issue 12

Abstract

Abstract The adult mammalian heart has limited regenerative capacity to replace lost tissue after a major injury. Forkhead box P1 (Foxp1) regulates embryonic cardiomyocyte proliferation and heart development. However, whether Foxp1 participates in postnatal‐injury cardiomyocyte proliferation and heart regeneration remains unclear. This study demonstrates that Foxp1 is downregulated at border zone cardiomyocytes of both neonatal apical resection and adult myocardial infarction. Analysis of the Single‐cell transcriptome database reveals reduced Foxp1 expression in the cardiomyocyte population with high regenerative capacity. Cardiomyocyte‐Foxp1 loss‐of‐function significantly promotes, whereas cardiomyocytes‐Foxp1 gain‐of‐function suppresses cardiomyocyte proliferation. Mechanistically, Foxp1 directly regulates ubiquitin specific peptidase 20 (USP20), a de‐ubiquitinase that prevents hypoxia inducible factor 1ɑ (HIF1α) degradation. Thus, Foxp1 regulates HIF1α and downstream heart and neural crest derivatives expressed 1 (Hand1) to control the cardiomyocyte proliferation via metabolic transition from fatty acid oxidation to glycolysis. Finally, cardiac type troponin T2 (cTnT)‐promoter‐driven adeno‐associated virus 9 (AAV9) for Hand1 induction in cardiomyocytes significantly promoted cardiac regeneration and functional recovery. These findings may provide novel molecular strategies to promote heart regeneration and therapeutic interventions for heart failure.
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Research context

OpenAlex topics: Congenital heart defects research · Cardiovascular Function and Risk Factors · Cardiac Fibrosis and Remodeling

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center Shanghai Heart Failure Research Center Department of Cardiovascular Surgery Shanghai East Hospital Tongji University School of Medicine Shanghai 200120 China

Department of Cardiology The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College) Wuhu Anhui 241001 China

Institute of Translational Medicine Baotou Central Hospital Baotou Inner Mongolia 014040 China

Department of Physiology and Pathophysiology School of Basic Medical Sciences Fudan University Shanghai 200032 China

Department of Trauma Shanghai East Hospital Tongji University School of Medicine Shanghai 200120 China

Faculty of Medicine Macau University of Science and Technology Macau SAR 999078 China

Division of Cardiology Department of Internal Medicine Wan Fang Hospital Taipei Medical University Taipei Taiwan 11696 China

Depeartment of Nephrology Shanghai East Hospital Shanghai 200120 China

Department of Medicine Rhode Island Hospital and Warren Alpert Medical School of Brown University Providence Rhode Island USA

Shenzhen Ruipuxun Academy for Stem Cell and Regenerative Medicine Shenzhen Guangdong 518122 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Shanghai Rising-Star Program · Natural Science Foundation of Guangdong Province

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