PLXNB2 (plexin B2) is a transmembrane receptor that functions as a critical mediator of cell-cell interactions and tissue homeostasis. As a receptor for class 4 semaphorins (SEMA4C, SEMA4D, SEMA4G, SEMA4A) 1, PLXNB2 activates downstream RhoA signaling and regulates actin cytoskeleton dynamics to control cell migration and morphology 2. Beyond semaphorin signaling, PLXNB2 serves as a receptor for angiogenin, promoting its endocytosis and enabling endothelial cell protection through ribosomal RNA transcription maintenance 3. It also functions as a receptor for grancalcin, triggering mitochondrial dysfunction and cellular senescence 4. Clinically, PLXNB2 has emerged as a therapeutic target in multiple diseases. In neuroinflammation, the microglia-astrocyte Sema4D-PlexinB2 axis drives pathogenic inflammation in experimental autoimmune encephalomyelitis 2. In cancer, activating G842C mutations sustain stem cell self-renewal and invasiveness in cancers of unknown primary through EGFR-dependent mechanisms 5. PLXNB2 promotes homotypic tumor cell clustering and heterotypic tumor-monocyte interactions critical for breast cancer metastasis 1, and guides glioblastoma invasion through microglia alignment 6. Additionally, hepatocyte-derived PLXNB2 constrains colorectal and pancreatic cancer liver colonization via semaphorin-mediated epithelialization 7, while the CD100-PLXNB2 axis amplifies psoriatic inflammation 8. These diverse roles position PLXNB2 as a multifunctional hub in tissue homeostasis and disease pathogenesis.