HEY2 is a Notch-responsive transcriptional repressor that plays critical roles in cardiovascular development and metabolic homeostasis. As a basic helix-loop-helix transcription factor, HEY2 binds preferentially to canonical E-box sequences (5'-CACGTG-3') and functions as a transcriptional repressor, likely through interaction with histone deacetylase complexes 1. In the heart, HEY2 regulates the transmural electrophysiological gradient and is associated with ion channel expression, particularly KCNIP2 which encodes the transient outward current subunit 2. Beyond electrical function, HEY2 directly represses genes controlling mitochondrial oxidative metabolism, including Ppargc1a and Esrra, and its upregulation impairs mitochondrial respiration and promotes cardiomyocyte apoptosis 3. HEY2 is essential for arteriovenous endothelial differentiation, with its expression marking arterial identity and controlling EphrinB2 expression 4. Germline HEY2 loss-of-function variants cause severe congenital heart defects including ventricular septal defects, while heterozygous carriers develop diverse cardiovascular pathologies including thoracic aortic aneurysms 5. Additionally, HEY2 suppresses neural fate specification in fibroblasts, and its knockdown facilitates neuronal transdifferentiation 6. HEY2's association with Brugada syndrome susceptibility 2 and its enrichment in endothelial progenitor cells 7 highlight its multifaceted importance in vascular biology and cardiac disease pathogenesis.