BEST3 (bestrophin 3) encodes a calcium-activated chloride channel that mediates chloride ion transport across cell membranes 1. The channel is regulated by its C-terminal domain, which contains an autoinhibitory sequence and basic amino acid residues that modulate activation through membrane phospholipid binding 2. BEST3 is activated by PI3K inhibitors and plays a critical role in vascular physiology 1. Mechanistically, BEST3 interacts with MEKK2/3 kinases to suppress their phosphorylation-dependent degradation, thereby regulating smooth muscle cell phenotype and vascular integrity 3. Alternative splicing generates a non-functional variant (Best3-Delta2,3,6) in exocrine glands that lacks the N-terminus and transmembrane domains, suggesting tissue-specific regulation 4. Clinically, BEST3 deficiency in vascular smooth muscle cells causes spontaneous aortic dissection in mice (48% incidence by 72 weeks), with human aortic dissection samples showing reduced BEST3 expression 3. BEST3 overexpression in non-small cell lung cancer promotes tumor cell proliferation and migration while suppressing apoptosis, implicating it as a prognostic marker 5. A rare BEST3 missense variant (L606I) has been identified in mandibular prognathism 6. BEST3-MEKK2/3 signaling represents a novel therapeutic target for aortic dissection.