The longevity protein p66Shc is required for neonatal heart regeneration.

The longevity protein p66Shc is essential for the senescence signaling that is involved in heart regeneration and remodeling. However, the exact role of p66Shc in heart regeneration is unknown. In this study, we found that p66Shc deficiency decreased neonatal mouse cardiomyocyte (CM) proliferation and impeded neonatal heart regeneration after apical resection injury. RNA sequencing and functional verification demonstrated that p66Shc regulated CM proliferation by activating β-catenin signaling. These findings reveal the critical role of p66Shc in neonatal heart regeneration and provide new insights into senescence signaling in heart regeneration.