biostudies-literatureUnknown13(1)Zhang DPyruvate kinase M1 (PKM1) is a critical enzyme in glycolysis, particularly in high-energy-demand tissues like the heart. However, previous knockout strategies for PKM1 were confounded by compensatory upregulation of its low-activity splice variant, PKM2. Here, we generated a <i>Pkm1</i> mutant mouse model using a point mutation that eliminates PKM1 without compensatory PKM2 upregulation. Homozygous <i>Pkm1</i> mutants exhibited perinatal lethality associated with cardiac dysfunction, characterized by thin myocardium and reduced cardiomyocyte proliferation during mid-to-late gestation. We found that PKM1 sustains ATP levels to inhibit AMPK, which otherwise promotes NFYa phosphorylation and destabilization. NFYa, a transcription factor essential for cardiomyocyte proliferation, has been idenNational science reviewnwaf408https://www.ebi.ac.uk/biostudies/studies/S-EPMC12796809biostudies-literaturePKM1 is required for embryonic cardiomyocyte proliferation through energetic regulation of NFYa stability.PMC12796809Liu JZhang DXu DYe WWang HYang DHuang RZhao YQin SSu NShi GKou XTang YGao SKang LWei KfalsePKM1 is required for embryonic cardiomyocyte proliferation through energetic regulation of NFYa stability.Pyruvate kinase M1 (PKM1) is a critical enzyme in glycolysis, particularly in high-energy-demand tissues like the heart. However, previous knockout strategies for PKM1 were confounded by compensatory upregulation of its low-activity splice variant, PKM2. Here, we generated a <i>Pkm1</i> mutant mouse model using a point mutation that eliminates PKM1 without compensatory PKM2 upregulation. Homozygous <i>Pkm1</i> mutants exhibited perinatal lethality associated with cardiac dysfunction, characterized by thin myocardium and reduced cardiomyocyte proliferation during mid-to-late gestation. We found that PKM1 sustains ATP levels to inhibit AMPK, which otherwise promotes NFYa phosphorylation and destabilization. NFYa, a transcription factor essential for cardiomyocyte proliferation, has been iden2026-01-01T00:00:00Z2026 Jan2026-06-03T03:15:04.53Z2026-06-03T03:10:39.164ZS-EPMC127968094153630510.1093/nsr/nwaf408