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Introduction:Permanent loss of cardiomyocytes (CM) after myocardial infarction (MI) and limited cardiac regenerative capacity lead to heart failure. The iPSC-derived extracellular vesicles (EV) have been shown to improve cardiac function and protection. However, the iPSC-EVs-mediated cardiac function improvement mechanism remains unclear and largely pertains to microRNAs and other RNAs, with a little elucidation of the role of iPSC-EV proteins.Hypothesis:The myocardial delivery of hiPSC-EV-specific protein PSAT1 (phosphoserine aminotransferase 1) induced cardiac regeneration and improved cardiac function post-MI by activating CM proliferation and anti-oxidative stress molecular pathways.Methods and Results:We show that hiPSC-EVs treatment augmented cardiac functions and induced a significant CM cell cycle in mice post-MI. Proteomic analysis identified PSAT1 as a protein expressed exclusively in hiPSC-EVs. The role of PSAT1 in CM proliferation and cardiac regeneration is not studied. The PSAT1 expression was significantly downregulated with heart development. Cardiac delivery of PSAT1 modified mRNA (modRNA) induced a significant CM proliferation post-MI. This increase in the CMs proliferation by the PSAT1 modRNA was associated with reduced scar size, improved cardiac function and CM survival, reduced oxidative stress, and CM apoptosis post-MI. Furthermore, the PSAT1 modRNA inhibited the CM apoptosis by reducing oxidative stress and DNA damage response post-MI. Moreover, we show that the YAP, a master regulator of CM proliferation and cardiac regeneration, binds to the promoter of PSAT1 and induces its expression. Finally, PSAT1 modRNA induced the serine biosynthesis pathway in CMs, resulting in increased nucleotide synthesis and reduced oxidative stress, thereby supporting CM proliferation.Conclusion:Our studies uncover a novel role of hiPSC-EV specific protein PSAT1, and serine synthesis pathway activation leads to post-MI CM proliferation, inhibition of oxidative stress, and improved cardiac function. Furthermore, this work emphasizes the therapeutic prospect of using PSAT1 modRNA as a gene delivery approach for ischemic heart diseases.