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Forkhead box P1 (Foxp1) regulates embryonic cardiomyocyte proliferation and heart development. However, whether Foxp1 participates in postnatal\u2010injury 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\u2010cell transcriptome database reveals reduced Foxp1 expression in the cardiomyocyte population with high regenerative capacity. Cardiomyocyte\u2010Foxp1 loss\u2010of\u2010function significantly promotes, whereas cardiomyocytes\u2010Foxp1 gain\u2010of\u2010function suppresses cardiomyocyte proliferation. Mechanistically, Foxp1 directly regulates\u00a0ubiquitin specific peptidase 20 (USP20), a de\u2010ubiquitinase that prevents hypoxia inducible factor 1\u0251 (HIF1\u03b1) degradation. Thus, Foxp1 regulates HIF1\u03b1 and downstream heart and neural crest derivatives expressed 1\u00a0(Hand1) to control the cardiomyocyte proliferation via metabolic transition from fatty acid oxidation to glycolysis. Finally, cardiac type troponin T2 (cTnT)\u2010promoter\u2010driven adeno\u2010associated 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.<\/jats:p>","DOI":"10.1002\/advs.202412124","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T14:34:11Z","timestamp":1738593251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cardiomyocyte Foxp1\u2010Specific Deletion Promotes Post\u2010injury Heart Regeneration via Targeting Usp20\u2010HIF1\u0251\u2010Hand1 Signaling Pathway"],"prefix":"10.1002","volume":"12","author":[{"given":"Yanfang","family":"Wang","sequence":"first","affiliation":[{"name":"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"},{"name":"Department of Cardiology The First Affiliated Hospital 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