MAP3K3 (mitogen-activated protein kinase kinase kinase 3) is a serine/threonine protein kinase that functions as a critical regulator of multiple cellular processes through distinct signaling pathways. In vascular biology, MAP3K3 plays a central role in cerebral cavernous malformation (CCM) pathogenesis, where somatic activating mutations (particularly I441M) are found in approximately 40-90% of sporadic CCM cases 12. The mutant MAP3K3 promotes endothelial apoptosis and disrupts normal vascular development by activating KLF2/KLF4 transcription factors and increasing Rho activity 3. In cancer, MAP3K3 acts as an oncogene when amplified in 8-20% of breast cancers, promoting cell survival and chemotherapy resistance 4. Additionally, MAP3K3 regulates YAP protein stability through phosphorylation at serine 405, preventing its lysosomal degradation and contributing to resistance against BRAF and CDK4/6 inhibitors 5. In inflammatory conditions, MAP3K3 facilitates myeloid cell diapedesis during myocardial ischemia/reperfusion injury through the TAL1/JAM-A pathway 6. These diverse functions highlight MAP3K3 as a potential therapeutic target across vascular malformations, cancer, and inflammatory diseases, with inhibitors like pazopanib showing promise in preclinical studies.