Article Impact Level: HIGH Data Quality: STRONG Summary of Theranostics, 15(15), 7219–7241. https://doi.org/10.7150/thno.112077 Dr. Ajit Magadum et al.
Points
- The developmental gene PSAT1 was reactivated using synthetic modified mRNA to promote significant heart repair and regeneration following myocardial infarction in a preclinical model.
- Direct delivery of PSAT1-modRNA to the heart led to robust cardiomyocyte proliferation, enhanced blood vessel formation, and a notable reduction in post-infarct scar tissue size.
- Mechanistically, PSAT1 activates the serine synthesis pathway, which enhances nucleotide production for cell division and significantly mitigates the damaging effects of oxidative stress on heart cells.
- The study revealed that YAP1 transcriptionally regulates PSAT1 and is indispensable for inducing β-catenin nuclear translocation, essential for cardiomyocyte cell cycle re-entry.
- These findings establish PSAT1-modRNA as a promising new therapeutic strategy for ischemic heart disease, offering a non-viral, regenerative approach to repair damaged cardiac muscle tissue.
Summary
This study investigated the therapeutic potential of phosphoserine aminotransferase 1 (PSAT1), a gene highly expressed in embryonic development but downregulated postnatally, for cardiac repair. Researchers delivered synthetic PSAT1-modified mRNA (modRNA) directly into the hearts of mice following myocardial infarction (MI) to assess its effects. The primary objective was to determine if reactivating this developmental gene could stimulate regenerative pathways, including cell proliferation, survival, and angiogenesis, that are typically dormant in the adult heart.
The results demonstrated that intracardiac injection of PSAT1-modRNA after myocardial infarction (MI) led to a significant increase in cardiomyocyte proliferation, enhanced angiogenesis, and a reduction in scar tissue formation. These structural improvements translated to superior cardiac function and increased survival rates in treated mice compared to controls. Mechanistically, PSAT1 was found to activate the serine synthesis pathway (SSP), which increased nucleotide synthesis for cell division and reduced oxidative stress and DNA damage, thereby inhibiting cardiomyocyte apoptosis.
Further molecular investigation revealed that PSAT1 is a downstream target of the regenerative factor YAP1 and is indispensable for YAP1-induced cardiomyocyte proliferation. PSAT1, in turn, promotes the nuclear translocation of β-catenin, a critical step for cell cycle re-entry. Inhibition of the SSP abrogated the pro-proliferative and anti-apoptotic effects of PSAT1, confirming the pathway’s central role in these processes. These findings establish PSAT1 as a pleiotropic regulator of cardiac repair, positioning PSAT1-modRNA as a promising, non-integrating therapeutic strategy for ischemic heart disease.
Link to the article: https://www.thno.org/v15p7219.htm
References Magadum, A., Mallaredy, V., Roy, R., Joladarashi, D., Thej, C., Cheng, Z., Cimini, M., Truongcao, M., Chatoff, A., Crispim, C. V., Rigaud, V. O. C., Gonzalez, C., Benedict, C., Santos, C. X. C., Snyder, N. W., Khan, M., Shah, A. M., Koch, W. J., & Kishore, R. (2025). Phosphoserine aminotransferase 1 promotes serine synthesis pathway and cardiac repair after myocardial infarction. Theranostics, 15(15), 7219–7241. https://doi.org/10.7150/thno.112077
