The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family regulates fundamental processes in both innate and adaptive immunity. Aberrant NF-κB activation, whether through canonical or non-canonical signaling pathways, contributes to chronic inflammation, autoimmunity, allergy, and primary immunodeficiency/autoinflammatory syndromes, while also influencing host defense and tissue repair mechanisms. The present review aims to synthesize molecular architecture, upstream triggers, ubiquitin-centered relay systems, and the dynamic regulation of NF-κB activity. The major findings on the NF-κB signaling pathway encompass its dual molecular mechanisms (canonical and non-canonical), its central roles in immune and inflammatory responses, cell survival, and development, as well as its complex regulatory networks. We interpret NF-κB as a master integrator of diverse signals, essential for both acute and long-term physiological processes. Dysregulation of NF-κB underlies many diseases, and while it is a promising therapeutic target, its ubiquitous functions demand precise modulation to avoid adverse effects. In conclusion, the proper function of the NF-κB signaling pathway is essential for maintaining cellular homeostasis and immune defense; its dysregulation is linked to chronic inflammatory diseases, autoimmune disorders, and cancer, which underscores the pathway’s significance as a therapeutic target. Although it elucidates molecular processes and treatment options, experimental validation of emerging therapeutic concepts such as ubiquitin code editing and spatial immunology remains limited.
Sharma et al. (2026) studied this question.