SEMA4D (semaphorin 4D) is a transmembrane signaling molecule that functions as a key mediator of cell-cell communication across multiple biological systems. The protein serves as a ligand for plexin receptors, particularly PLXNB1 and PLXNB2, to regulate diverse cellular processes. In the nervous system, SEMA4D controls microglial-astrocyte interactions during neuroinflammation, where microglia-expressed SEMA4D activates astrocytes via PlexinB2 to promote pathological responses in experimental autoimmune encephalomyelitis 1. The protein also regulates transcription of inflammatory genes including STAT3, CCL5, and IRF1 in activated microglia during autoimmune uveitis 2. In vascular biology, SEMA4D/PlexinB1 signaling induces endothelial dysfunction and contributes to diabetic retinopathy pathogenesis, with soluble SEMA4D levels correlating with poor anti-VEGF treatment response 3. Additionally, SEMA4D promotes choroidal neovascularization in age-related macular degeneration through CD8+ T cell-pericyte interactions 4. In cardiovascular disease, osteoclast-derived SEMA4D drives sympathetic hyperinnervation, promoting vascular smooth muscle cell phenotypic switching and abdominal aortic aneurysm development 5. SEMA4D also serves as a biomarker for hepatic fibrosis in metabolic dysfunction-associated steatotic liver disease 6 and facilitates osteoblast-osteoclast communication in bone remodeling 7.