NFIL3 (nuclear factor, interleukin 3 regulated), also known as E4BP4, is a bZIP transcription factor that functions as both a transcriptional repressor and activator. It recognizes and binds DNA sequences (5'-[GA]TTA[CT]GTAA[CT]-3') present in cellular and viral promoters, competing with PAR family factors (DBP, HLF, TEF) for binding sites 1. NFIL3 represses transcription from ATF-site-containing promoters and negatively regulates circadian clock components PER1 and PER2, functioning as a core circadian rhythm regulator 2. It activates IL-3 transcription in T cells and positively regulates immune cell development, including natural killer cells and dendritic cell lineage specification through Zeb2 enhancer regulation 3. NFIL3 suppresses proinflammatory cytokine production and restrains acute inflammatory responses, with expression enhanced within nuclear stress bodies during cellular stress 4. In immune contexts, NFIL3 serves as an accessory transcription factor in regulatory T cell specification and CD8+ T cell programming through epigenetic regulation of TCF1 5. Emerging evidence links NFIL3 to metabolic homeostasis and atherosclerosis progression through regulation of lipid metabolism and macrophage polarization 6. NFIL3 acts upstream of multiple developmental pathways, with transient expression during differentiation of myeloid progenitors into conventional dendritic cells 3.