-PDE10A contributed to DOX-induced mouse cardiomyocyte death via increasing Top2β expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG signaling.-PDE10A contributed to mouse cardiomyocyte atrophy via potentiating FoxO3 signaling via both cAMP/PKA and cGMP/PKG dependent signaling.-PDE10A inhibition alleviated DOX-induced myocardial atrophy and apoptosis.-PDE10A inhibition increased the death, potentiated the effect of DOX on various human cancer cells. Here, PRKG1 is linked to Atrophy.