PDE3A is a cyclic nucleotide phosphodiesterase that hydrolyzes cAMP and cGMP, key second messengers regulating diverse physiological processes 1234. Beyond its catalytic function, PDE3A participates in estrogen-induced apoptosis by stabilizing the PDE3A/SLFN12 complex, promoting SLFN12 dephosphorylation and activating its pro-apoptotic ribonuclease activity, potentially relevant in placental remodeling 56. In oocyte maturation, cGMP from cumulus cells inhibits PDE3A, maintaining elevated cAMP that blocks meiosis. During the LH surge, reduced cGMP removes this inhibition, allowing PDE3A to hydrolyze cAMP and trigger meiotic resumption 78. In platelets, thrombospondin-1 increases PDE3A activity to suppress cAMP-mediated inhibition of platelet aggregation 9. Gain-of-function PDE3A mutations cause hypertension with brachydactyly (HTNB), increasing vascular smooth muscle proliferation and vascular resistance 1011. Paradoxically, these mutations provide cardiac protection despite prolonged hypertension by altering local cAMP signaling and calcium handling in cardiomyocytes 10. Clinically, PDE3A-SLFN12 complex induction shows anti-cancer potential 12, though a first-in-human trial of PDE3A-SLFN12 inducer BAY 2666605 was terminated due to mechanism-based thrombocytopenia 13.