RAPGEF3 encodes EPAC1 (exchange protein directly activated by cAMP), a cAMP-responsive guanine nucleotide exchange factor that activates RAP1A and RAP2A small GTPases 1. EPAC1 functions as a cAMP sensor mediating intracellular signaling through dynamic signalosomes formed with diverse cellular partners 1. Mechanistically, EPAC1 regulates multiple physiological processes including adipogenesis, where selective pharmacological activation increases brown adipose tissue mass and browning of white fat, reducing diet-induced obesity 2. In podocytes, EPAC1 activation protects against glomerulonephritis by reprogramming cellular metabolism through enhanced mitochondrial function and glycolysis 3. EPAC1 also promotes autophagy in pancreatic β-cells via calcium-dependent signaling through calcineurin and TFEB, supporting cell survival under metabolic stress 4. In vascular endothelium, EPAC1 activation restores endothelial function during inflammation by suppressing IL-6-mediated pro-inflammatory responses and upregulating nitric oxide synthase 5. Clinically, RAPGEF3 variants associate with obesity risk: a coding variant correlates positively with BMI and abolishes noradrenaline-induced brown adipocyte proliferation 2, while rare variants show ~10-fold larger BMI effects than common variants 6. In pulmonary fibrosis, EPAC1 inhibition with AM-001 protects against progression by blocking profibrotic pathways 7. In lung cancer, RAPGEF3 drives basal-subtype progression via RAP1A-AKT signaling and represents a therapeutic vulnerability amenable to selective inhibition 8.