SEMA4B (semaphorin 4B) is a membrane-bound protein that functions as a key regulator of cell growth, migration, and invasion across multiple disease contexts. Primary function: SEMA4B inhibits axonal extension and provides chemorepellent signals through semaphorin-plexin signaling pathways 1. Mechanism: SEMA4B suppresses PI3K/Akt signaling to inhibit cell proliferation. In non-small cell lung cancer (NSCLC), SEMA4B decreases MMP9 expression via PI3K pathway inhibition, reducing metastatic potential 2. SEMA4B also induces FoxO1 nuclear retention to suppress growth through p21-mediated cell cycle arrest 1. A novel circular RNA (circSEMA4B) encodes SEMA4B-211aa protein, which inhibits AKT phosphorylation through p85 binding 3. Disease relevance: SEMA4B expression is paradoxically altered across cancers—decreased in NSCLC where it acts tumor-suppressive 1, but elevated in lung adenocarcinoma where it paradoxically promotes progression by enhancing myeloid-derived suppressor cell infiltration 4. Chr15 chr15 exposure suppresses SEMA4B methylation, promoting malignant transformation of bronchial epithelial cells 5. In rheumatoid arthritis, SEMA4B is elevated and enhances inflammatory macrophage and fibroblast-like synoviocyte phenotypes via PlexinB2 6. Clinical significance: SEMA4B is a promising therapeutic target, with downregulation by hypoxia-HIF-1 axis driving NSCLC invasion 7.