ArticleScience advances2025
Blocking nuclear receptor Nr4a3 unlocks the senescence barrier to promote direct cardiac reprogramming.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Integrating delivery systems and microenvironmental cues to accelerate clinical translation of cardiac reprogramming.Materials today. Bio · 2026Review
- Epigenetic dynamics of cellular senescence: From mechanistic insights to precision senotherapy.Chinese medical journal · 2026Review
- Multicellular senescence programs in the aged heart.Journal of molecular and cellular cardiology plus · 2026Review
- Enhanced Neuromodulation Using PC-CNTs and NIR Photothermal Therapy for Preventing Ventricular Arrhythmias.International journal of nanomedicine · 2026Article
- AP39 alleviates HHCY-induced myocardial remodeling by regulating FUNDC1-mediated mitochondrial dynamics via S-sulfhydration of NEDD8/CUL4B.Frontiers in pharmacology · 2026Article
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) offers a regenerative strategy for heart repair, but efficiency declines in adult and aged cells. Transcriptomic and epigenetic profiling identified cellular senescence as a major barrier limiting cardiac fibroblast (CF) plasticity and cardiogenic conversion. Postneonatal fibroblasts exhibited impaired activation of cardiac gene programs and persistent expression of fibrotic and inflammatory signatures. A loss-of-function screen identified Nr4a3 as a central repressor. Nr4a3 overexpression promoted senescence and suppressed iCM induction, whereas knockdown enhanced reprogramming in murine and human senescent CFs. Mechanistically, Nr4a3 depletion remodeled the chromatin landscape from a fibrotic and inflammatory state to a regenerative cardiac program. Blocking downstream Cxcl14 restored reprogramming in refractory fibroblasts. In vivo, Nr4a3 knockdown improved heart function following myocardial infarction. These findings established cellular senescence as a major barrier to cardiac reprogramming and identified Nr4a3 and its effectors as potential targets to enhance heart regeneration.
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Registered trials
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