Ryanodine receptor 2 (RYR2) dysfunction activates the unfolded protein response and perturbs cardiomyocyte maturation.

Dysfunctional calcium handling is a major factor contributing to cardiac pathogenesis, but the molecular mechanisms remain unclear. This study uncovered RYR2 as a new regulator of ER stress and cardiomyocyte maturation, providing significant insights to guide the development of therapeutic approaches to control cardiac pathogenesis. Because cardiomyocyte maturation is a major bottleneck in translational medicine using stem cell-derived cardiomyocytes, this study also pointed out RYR2 and ER homeostasis as potential targets to manipulate the maturity of stem cell-derived cardiomyocytes.