SEMA6A (semaphorin 6A) is a transmembrane guidance protein that plays crucial roles in vascular regulation, neural development, and cellular signaling. In vascular biology, SEMA6A functions as a negative regulator of angiogenesis through phase separation mechanisms, where its C-terminal intrinsically disordered region forms liquid-liquid condensates that recruit RHOA and P300, facilitating histone lactylation cycles that sustain pathological angiogenesis 1. The protein controls median eminence vascular permeability via its receptor Plexin-A2, which is essential for GnRH neuron innervation and puberty onset 2. SEMA6A mediates cytoskeletal organization through interaction with EVL (Ena/VASP-like protein) via a novel carboxyl-terminal zyxin-like domain, suggesting involvement in retrograde signaling pathways 3. In cancer biology, SEMA6A promotes tumor progression through multiple mechanisms: it stabilizes β-catenin via SEC62 interaction in clear cell renal cell carcinoma as a HIF-2α target gene 4, and controls cell survival and growth in BRAF-mutant melanoma through cytoskeletal remodeling 5. Genetic variants in SEMA6A are associated with delayed puberty in humans 2, vasculitis susceptibility 6, and exfoliation syndrome 7, highlighting its clinical significance in multiple pathological conditions.