HEG1 (heart development protein with EGF-like domains 1) is a multifunctional endothelial and epithelial protein with critical roles in cardiovascular homeostasis and disease pathogenesis. As a component of the CCM (cerebral cavernous malformation) signaling pathway, HEG1 regulates endothelial cell junction stability and vascular integrity 1. Mechanistically, HEG1 functions as a shear stress-sensitive mediator: stable blood flow induces HEG1 expression, which then translocates to endothelial cells and regulates the MEKK3-MEK5-ERK5-MEF2 pathway to promote KLF2/4 expression, ultimately enhancing NO production and vasodilation 12. At the molecular level, HEG1 facilitates CUL3-mediated degradation of PHACTR1, thereby promoting eNOS transcription and maintaining endothelial function 2. Clinically, reduced HEG1 expression associates with atherosclerosis development and hypertension; HEG1-knockout mice exhibit accelerated atherosclerotic plaques and elevated blood pressure 12. Beyond cardiovascular disease, HEG1 serves as a diagnostic marker for mesothelioma (91% sensitivity, 99.7% specificity) 3 and as a prognostic biomarker in lung adenocarcinoma, where downregulation correlates with poor survival 4. In malignant mesothelioma, HEG1 supports cell proliferation through miR-23b-mediated evasion of apoptosis 5. These findings establish HEG1 as a potential therapeutic target for cardiovascular and malignant diseases.