Emerging role of E4BP4/NFIL3 in metabolic homeostasis

E4BP4/NFIL3 (E4 promoter-binding protein 4 or nuclear factor interleukin-3-regulated protein), is well-established for its association with circadian rhythm regulation and immune function. Recent advances in research have revealed its emerging and indispensable role in metabolic homeostasis, positioning it at the crossroads of circadian biology, immune responses, and metabolic balance. This review summarizes three decades of research on E4BP4/NFIL3 and explores its structural basis and regulatory functions. We synthesized current insights into the regulatory pathways that govern E4BP4/NFIL3 and discuss its central role in various metabolic scenarios, emphasizing its emerging significance as a pivotal metabolic regulator. Finally, we identify critical, unresolved questions and propose future research directions to enhance our understanding of E4BP4/NFIL3's broader implications in metabolic health.