FAM76B is a 39 kDa nuclear speckle-localized protein that negatively regulates inflammatory pathways through two distinct mechanisms 1. First, FAM76B inhibits NF-κB-mediated inflammation by preventing the cytoplasmic translocation of hnRNPA2B1, a nuclear-to-cytoplasm transport regulator 2. Second, FAM76B stabilizes PIK3CD mRNA, elevating PIK3CD protein levels and downstream phosphorylated AKT, which suppresses NF-κB signaling and reduces M1 macrophage polarization 3. FAM76B exhibits phase separation properties dependent on its histidine-rich region, with deletion of this region paradoxically enhancing macrophage-mediated anti-tumor immunity 4. Functionally, FAM76B knockout increases M1 macrophage markers and inflammatory responses in vitro 3. In vivo, FAM76B protects against inflammatory bowel disease by inhibiting M1 macrophage polarization and suppresses neuroinflammation in traumatic brain injury models 23. FAM76B is conserved across species and expressed in most human organs at varying levels 1. Genetic variants near FAM76B associate with sun-seeking behavior, linking it to behavioral traits 5. FAM76B has been identified in rare disease-associated fusions, including in Ewing sarcoma and other malignancies 67.