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Synthesize nearly four decades of NF-κB research to delineate its molecular activation, crosstalk with other signaling networks, disease associations, and emerging therapeutic interventions.

March 4, 2024Signal Transduction and Targeted Therapy1,903 citationsOpen Access

NF-κB in biology and targeted therapy: new insights and translational implications

QGQing GuoShihezi University YJYizi JinShanghai Medical College of Fudan University XCXinyu ChenChongqing Medical University

Key Points

Synthesize nearly four decades of NF-κB research to delineate its molecular activation, crosstalk with other signaling networks, disease associations, and emerging therapeutic interventions.
Conducted a comprehensive narrative review of NF-κB structural composition, regulatory mechanisms, and signaling crosstalk with PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR pathways.
Evaluated pathological involvement across cancer, inflammatory, autoimmune, cardiovascular, metabolic, and neurological disorders, alongside therapeutic modalities including small-molecule inhibitors, biologics, and cellular therapies.
Characterized complex pathway cross-regulation demonstrating that NF-κB serves as a central hub integrating immune responses, cellular survival, and tumor microenvironment dynamics.
Identified diverse targeted therapeutic strategies against NF-κB nodes, including IKK inhibitors, proteasome inhibitors, nuclear translocation inhibitors, DNA binding blockers, tyrosine kinase inhibitors, and CAR-T cell immunotherapies.

Abstract

NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

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