Phosphoserine aminotransferase 1 promotes serine synthesis pathway and cardiac repair after myocardial infarction.

Background and Purpose: The permanent loss of cardiomyocytes (CMs) following myocardial infarction (MI), coupled with the heart's limited regenerative capacity, often leads to heart failure. Phosphoserine aminotransferase 1 (PSAT1) is a protein highly expressed in the embryonic mouse heart but markedly downregulated after birth. Despite its presence in early cardiac development, PSAT1's role in CM proliferation, cardiac physiology, and repair remains unexplored. This study investigates the therapeutic potential of PSAT1-modified mRNA (modRNA) for promoting cardiac repair and improving outcomes post-MI. Methods: Synthetic PSAT1-modRNA was delivered to the hearts of mice post-MI. The study evaluated its effects on CM proliferation and death, scar formation, angiogenesis, and cardiac function. Molecular mechanisms underlying PSAT1's actions were explored, including its regulation of the serine synthesis pathway (SSP), oxidative stress, nucleotide synthesis, and interactions with the YAP1-β-catenin molecular axis. Additionally, SSP inhibition studies were conducted to determine its contribution to CM cell cycle activity and apoptosis. Results: PSAT1 is downregulated during mouse heart development. Cardiac delivery of PSAT1-modRNA induced significant CM proliferation, reduced scar size, and enhanced angiogenesis. Functional analyses revealed improved cardiac performance and survival in PSAT1 injected mice post-MI. Mechanistically, PSAT1 induces the serine synthesis pathway (SSP) in CMs, resulting in increased nucleotide synthesis and reduced oxidative stress, thereby supporting CM proliferation and survival. Conversely, SSP inhibition suppressed CM cell cycle activity and triggered apoptosis post-MI. Furthermore, PSAT1 modRNA inhibited CM apoptosis by reducing oxidative stress and DNA damage. At the molecular level, YAP1 transactivated PSAT1, and PSAT1 induced β-catenin nuclear translocation, and is indispensable for YAP1-induced CM proliferation. Conclusions: PSAT1 emerges as a pleiotropic gene critical for favorable cardiac remodeling post-MI through multiple mechanisms, including CM proliferation, SSP activation, inhibition of oxidative stress and cell death, and YAP1-β-catenin pathway modulation. These findings highlight PSAT1's potential as a novel therapeutic target for mRNA-based treatments in ischemic heart diseases, offering a promising avenue for clinical application in cardiac repair.