PLXNB1 (plexin B1) is a transmembrane receptor for semaphorin ligands, particularly SEMA4D 12, that regulates cell-cell interactions across multiple physiological and pathological contexts. Mechanistically, PLXNB1 activates Rho GTPase signaling and modulates the actin cytoskeleton to control cell migration, axon guidance, and synapse development 345. In the nervous system, PLXNB1 mediates microglia-astrocyte interactions that influence CNS inflammation 6, and regulates peri-plaque glial spacing in Alzheimer's disease, affecting neuroinflammation and amyloid compaction 7. In vascular pathology, SEMA4D/PLXNB1 signaling promotes endothelial dysfunction and vascular leakage in diabetic retinopathy 1 and drives pericyte activation in age-related macular degeneration exacerbated by smoking 2. In the cardiovascular system, osteoclast-derived SEMA4D activates PLXNB1 on sympathetic nerves to promote aortic aneurysm development 8. Clinically, PLXNB1 represents a therapeutic target: blocking PLXNB1 enhances immunotherapy efficacy in breast cancer by reprogramming tumor-associated macrophages and promoting CD8+ T cell infiltration 9, and PLXNB1/SEMA4D signaling mediates colorectal cancer liver metastasis through epithelial-immune cell crosstalk 10. Additionally, PLXNB1 has been identified as a druggable therapeutic target for migraine 11.