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Life sciences · Journal article
Circulation · August 25, 2026
Raises a question worth testing. It does not answer one.
This preclinical study identifies Nfyb overexpression and Nr3c1 inhibition as a dual-target mechanism to promote cardiomyocyte proliferation and cytokinesis after myocardial infarction in transgenic mice and engineered human tissue. The findings establish a proof-of-concept regulatory pathway but have not yet been tested in clinical trials or translated to human disease.
Preclinical multimodel mechanistic study using transgenic reporter mice, clonal analysis, and human engineered tissue. Transgenic laboratory mice (Aurkb-tdTomato cytokinesis reporter mice, Myh6-MerCreMer;MADM mice) and human engineered heart tissue. Intervention: Spatiotemporally controlled adeno-associated virus 9 system with drug-inducible Nfyb overexpression and CRISPR/enOsCas12f1-mediated Nr3c1 deletion. Compared with: Control mice without intervention.
Dual intervention synergistically increased new cardiomyocyte formation by >28-fold versus control, with 28% clustered Nr3c1 inhibition alone improved cardiac function and reduced infarct size in post-myocardial infarction mice Nfyb overexpression enhanced cardiomyocyte proliferation and post-myocardial infarction cardiac repair through cell-cycle gene transcription
Long-term safety, durability, and off-target effects of AAV9-delivered Nfyb/Nr3c1 intervention not addressed
This mechanism-focused preclinical work does not yet support clinical application. Researchers developing cardiac regenerative therapies should consider the Nfyb/Nr3c1 pathway as a candidate target, but additional translational and clinical validation is required before any therapeutic recommendation.
Preclinical mechanistic study in transgenic mice and engineered tissues identifying a dual regulatory pathway; no clinical trials, hard outcomes, or direct human translation reported.
As stated by the source record.
Quoted from the source exactly as published.
This mechanism-focused preclinical work does not yet support clinical application. Researchers developing cardiac regenerative therapies should consider the Nfyb/Nr3c1 pathway as a candidate target, but additional translational and clinical validation is required before any therapeutic recommendation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
BACKGROUND: Myocardial infarction can cause a massive loss of functional cardiomyocytes, yet effective strategies to stimulate cardiac regeneration remain lacking. A key barrier to adult cardiomyocyte proliferation appears to be cytokinesis inhibition. This study aimed to determine whether combining proliferation stimulators with the removal of cytokinesis-inhibitory constraints could unlock regenerative potential after myocardial infarction. METHODS: Transcriptomic profile from 5 regeneration models, including Aurkb -tdTomato cytokinesis reporter mice and Myh6 -MerCreMer;mosaic analysis with double markers (MADM), and cross-species comparative analysis were used to explore the regulatory networks for cardiomyocyte proliferation. MADM mice were used to evaluate cardiac regeneration by quantifying after cytokinesis new cardiomyocytes and clonal clusters. RESULTS: Integrative multimodel analysis revealed a dual regulatory control system for cardiomyocyte proliferation, along with key associated genes and transcriptional regulators. Nfyb was identified as an activator and Nr3c1 as a repressor of cardiomyocyte proliferation. Nfyb overexpression enhanced cardiomyocyte proliferation and post–myocardial infarction cardiac repair through propelling cell-cycle gene transcription. Nr3c1 inhibition promoted cardiomyocyte proliferation, improved cardiac function, and reduced infarct size. A spatiotemporally controlled adeno-associated virus 9 system combining drug-inducible Nfyb overexpression and CRISPR/enOsCas12f1–mediated Nr3c1 deletion efficiently induces cardiomyocyte proliferation. Clonal analysis using MADM mice showed that the dual intervention synergistically increased new cardiomyocyte formation (28% clustered, >28-fold versus control). The enhanced regenerative effect of the dual intervention was demonstrated in post–myocardial infarction mice and human engineered heart tissues. CONCLUSIONS: This work documents a dual-control paradigm of cardiomyocyte proliferation and establishes Nfyb / Nr3c1 cointervention as a putative new therapy to induce and control cardiac regeneration after injury.
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