PHGDH Orchestrates Cell Cycle Progression to Drive Cardiomyocyte Proliferation and Myocardial Regeneration via TGF-β/Smad Signalling Pathway.

The mature mammalian heart has limited ability for self-repair and regeneration. Here, we establish phosphoglycerate dehydrogenase (PHGDH) as a crucial key for cardiomyocyte proliferation, with diminishing expression during postnatal cardiac development. PHGDH overexpression promoted myocardial regeneration and cardiac function in apical resection-operated mice, whereas inhibition by NCT-503 inhibited these processes. In vitro, PHGDH stimulated the proliferation of cardiomyocytes (CMs), while NCT-503 abolished its effect. Mechanistically, PHGDH activated the cell cycle and TGF-β/Smad signalling. Moreover, PHGDH significantly enhances cardiac repair and stimulates cardiomyocyte proliferation in adult mice following myocardial infarction. Our study demonstrates that upregulating PHGDH promotes CM proliferation and myocardial regeneration, offering a promising therapeutic target for myocardial repair.