FLT4 (VEGFR3) is a receptor tyrosine kinase primarily expressed on lymphatic endothelial cells that mediates lymphangiogenesis and vascular development through binding VEGFC and VEGFD ligands 1. The receptor activates multiple intracellular signaling cascades including MAPK/ERK, PI3K-AKT, and JNK pathways to promote endothelial cell proliferation, survival, and migration 2. Beyond vascular function, FLT4 signaling coordinates immune responses by recruiting AMPK to regulate glycolytic reprogramming, autophagy, and inflammasome activation during bacterial clearance 2. FLT4 mutations account for approximately 2.3% of Tetralogy of Fallot cases, representing a significant genetic contributor to congenital heart disease 3. In cancer biology, FLT4 promotes tumor angiogenesis and metastasis; elevated FLT4 expression correlates with advanced colorectal cancer stage and poor survival, while FLT4 suppression inhibits metastatic dissemination 4. Additionally, FLT4 expression marks disease progression in lung adenocarcinoma metastasis through m6A-dependent RNA stabilization mechanisms 5. Cardiac lymphangiogenesis via FLT4 activation reduces post-myocardial infarction inflammation and improves functional recovery 6. Pathogenic FLT4 variants are implicated in lymphatic malformations and lymphedema development 7. These findings establish FLT4 as a critical node integrating vascular development, immune function, and disease progression.