Abstract Body: Neonatal hearts in several mammalian species possess a remarkable capacity for regeneration, a trait lost in adults. While transcriptomic analyses have provided insights into regenerative processes, proteins are the functional effectors for tissue repair; however, the mechanisms underlying dynamic proteome remodeling during neonatal tissue regeneration remain poorly understood. Our previous study identified a unique population of cardiomyocytes in the neonatal mouse heart with regeneration capacity. These cells display a distinct transcriptomic signature enriched in ribosomal and proteasomal pathway genes, suggesting that simultaneous enhancement of protein synthesis and degradation is associated with heart regenerative capacity. Indeed, we observed an acute increase in newly synthesized proteins and enhanced proteasomal activity in neonatal regenerative hearts post-myocardial infarction, which is a response absent in nonregenerative hearts. Mechanistically, we identified that the transcription co-activator YAP, highly expressed in regenerative neonatal cardiomyocytes, activates mTORC1 signaling through transcriptional regulation of amino acid metabolism, thereby enhancing protein synthesis. mTORC1 activation, in turn, upregulates Nrf1, a transcription factor essential for protein quality control through dual regulation of proteasome activity and autophagy. We show that mTORC1 and Nrf1 activation are responsible for increased protein synthesis and the unique maintenance of protein homeostasis in neonatal hearts after injury, which are required for heart regeneration. Our study provides insights into the mechanisms that drive proteome remodeling, offering fundamental insights into how neonatal cardiomyocytes rapidly adapt to injury stress and regulate protein anabolic and catabolic processes for self-renewal.