SEMA4A is a cell surface semaphorin that functions as a ligand for plexin receptors (PLXNB1, PLXNB2, PLXNB3, PLXND1) and neuropilin-1, mediating diverse physiological processes 1. In the nervous system, SEMA4A regulates synapse development by promoting inhibitory synapse formation via PLXNB1 and excitatory synapse formation via PLXNB2, while also providing axon guidance signals 1. In immune responses, SEMA4A enhances germinal center B cell differentiation and is upregulated during T cell activation, contributing to adaptive immunity 2. SEMA4A exerts niche-derived protection of myeloid-biased hematopoietic stem cells against inflammatory stress through plexin D1 signaling, preserving stem cell functional diversity 3. Additionally, SEMA4A inhibits angiogenesis 1. Pathologically, SEMA4A mutations cause cone-rod dystrophy and retinitis pigmentosa 4. In cancer, SEMA4A is essential for myeloma cell survival and represents a viable immunotherapy target; SEMA4A-directed CAR T cells show superior efficacy against BCMA-low tumors 56. Recent evidence links SEMA4A upregulation to depression-like behaviors and mood dysfunction through impaired myelination pathways 7.