Structured Graphical Abstract.

Activation of serine biosynthesis pathway with a dual kinase inhibitor treatment rescues DCM contraction deficit. A kinase inhibitor screening was conducted in iPSC-derived cardiomyocytes, and the resulting hits identified were combined into one single treatment, PPi, that improved the contractile response of the cells. Mechanistically, PPi activated the serine biosynthesis pathway, translating in turn into a more efficient mitochondrial respiration and energy production. Finally, PPi rescued DCM phenotype in multiple gene mutations associated to DCM.