The NF\u2011\u03baB family is a master regulator of innate and adaptive immunity. Its aberrant activation-via canonical or non\u2011canonical pathways-drives chronic inflammation, autoimmunity, allergies, and primary immunodeficiencies\/autoinflammatory syndromes. This review synthesizes the molecular architecture, ubiquitin\u2011based relay systems, and dynamic regulation of NF\u2011\u03baB, highlighting its dual pathways, roles in immune responses, cell survival, and development. NF\u2011\u03baB integrates diverse signals for both acute and long\u2011term physiology. Dysregulation underpins many diseases, making it a promising therapeutic target, yet its ubiquitous functions demand precise modulation. While molecular mechanisms and treatment options are discussed, emerging concepts like ubiquitin code editing and spatial immunology lack experimental validation.<\/p>\n
Introduction<\/p>\n
NF\u2011\u03baB controls genes involved in inflammation<\/a>, immunity, cell survival, and proliferation. Triggered by cytokines (TNF\u2011\u03b1, IL\u20111\u03b2), microbial products, or cellular stress, it translocates to the nucleus and induces pro\u2011inflammatory mediators. Acute activation clears pathogens and promotes tissue repair; chronic activation contributes to rheumatoid arthritis, inflammatory bowel disease (IBD), atherosclerosis, and cancer. NF\u2011\u03baB also supports immune cell development and tolerance, and defects in its signaling cause immunodeficiency or autoimmunity. The family comprises five proteins-RelA (p65), c\u2011Rel, RelB, p50, and p52-all sharing a conserved Rel homology domain. RelA, c\u2011Rel, and RelB possess transactivation domains, while p50\/p52 act as repressors; the predominant dimer is p50:RelA.<\/p>\n NF\u2011\u03baB signaling: Canonical and non\u2011canonical pathways<\/p>\n Under resting conditions, I\u03baB proteins (I\u03baB\u03b1, I\u03baB\u03b2, I\u03baB\u03b5) sequester NF\u2011\u03baB in the cytoplasm. Upon stimulation, the IKK complex (IKK\u03b1, IKK\u03b2, and NEMO) is activated; IKK\u03b2 phosphorylates I\u03baB\u03b1, leading to its ubiquitination and proteasomal degradation. This frees NF\u2011\u03baB for nuclear translocation, where it induces genes for inflammation (TNF\u2011\u03b1, IL\u20116, COX\u20112), survival (Bcl\u20112, IAPs), and proliferation (cyclin D1). A negative feedback loop via I\u03baB\u03b1 synthesis terminates the response.<\/p>\n The\u00a0canonical pathway\u00a0is triggered by TNF\u2011\u03b1, IL\u20111, Toll\u2011like receptors, and antigens; it relies on IKK\u03b2\/NEMO and I\u03baB\u03b1 degradation, releasing p50:RelA dimers rapidly and transiently. It is involved in chronic inflammation, autoimmunity, and cancer. The\u00a0non\u2011canonical pathway\u00a0is activated by BAFF\u2011R, CD40, and LT\u03b2R; it depends on NIK and IKK\u03b1 to process p100\u2192p52, releasing p52:RelB dimers slowly and sustainably. This pathway is critical for B\u2011cell maturation, lymphoid organogenesis, and tolerance, and its dysregulation is linked to autoimmunity and lymphoma.<\/p>\n Ubiquitin\u2011mediated relays are central to both pathways. K63\u2011linked and linear (M1) ubiquitin chains act as scaffolds to recruit kinases (TAK1, IKK). LUBAC generates M1 chains; E3 ligases (TRAF6, cIAP1\/2) build K63 chains. Deubiquitinases (A20, CYLD, OTULIN) remove chains to terminate signaling. Dysregulation of these enzymes causes immunodeficiency and autoinflammation.<\/p>\n Dysregulation in immunological diseases<\/p>\n In autoimmune diseases, NF\u2011\u03baB drives synovial inflammation and bone erosion in rheumatoid arthritis; chronic intestinal inflammation in IBD; autoreactive B and T cells in systemic lupus erythematosus; the TNF\/IL\u201123\/IL\u201117 axis in psoriasis; and airway remodeling in asthma. In primary immunodeficiencies and autoinflammatory syndromes, NEMO mutations cause ectodermal dysplasia with immunodeficiency or incontinentia pigmenti; LUBAC defects lead to combined immunodeficiency with autoinflammation and glycogen storage disease; and A20 haploinsufficiency results in early\u2011onset Beh\u00e7et\u2011like autoinflammation.<\/p>\n Emerging research also links NF\u2011\u03baB to metabolic reprogramming (upregulation of glycolytic genes, Warburg effect), cellular stress responses, and resistance to immune checkpoint inhibitors through mechanisms such as defective antigen presentation, interferon\u2011\u03b3 mutations, and an immunosuppressive tumor microenvironment. NF\u2011\u03baB crosstalks extensively with JAK\u2011STAT, MAPK, PI3K\u2011AKT, Wnt\/\u03b2\u2011catenin, and Notch pathways, diversifying outcomes and potentially causing resistance to single\u2011agent therapies.<\/p>\n Therapeutic strategies and biomarkers<\/p>\n Approved indirect strategies include anti\u2011cytokine biologics (anti\u2011TNF, anti\u2011IL\u20111, anti\u2011IL\u20116), BTK inhibitors, and proteasome inhibitors (bortezomib) that block I\u03baB degradation. Emerging direct strategies target IKK\u03b2\/NEMO (potent but toxic, requiring tissue\u2011targeted delivery), NIK (for non\u2011canonical pathway), MALT1 (for lymphocyte\u2011driven diseases), and DUB modulators to restore negative regulation. Novel delivery technologies-nanoparticles, PROTACs, HDAC inhibitors, and miRNA\/lncRNA therapeutics-aim to improve selectivity and reduce toxicity.<\/p>\n Biomarkers and translational readouts include tissue assays (nuclear p65, phospho\u2011I\u03baB\/IKK, RelB\/p52 localization), molecular signatures from gene expression profiling, and functional dynamics techniques (live\u2011cell imaging, single\u2011cell multi\u2011omics, mathematical modeling) that capture temporal patterns of NF\u2011\u03baB activity. These tools aid diagnosis, prognosis, and patient selection for targeted therapies.<\/p>\n Future directions and conclusion<\/p>\n Emerging concepts include dynamics\u2011guided precision therapy, ubiquitin code editing, spatial immunology, tissue\u2011targeted delivery, genotype\u2011to\u2011therapy approaches, and combination logic to co\u2011target multiple nodes. This review moves beyond linear signaling to embrace a dynamic, precision\u2011targetable network. Limitations include insufficient experimental validation for emerging approaches, unresolved toxicity and specificity issues, and limited clinical biomarker<\/a> validation.<\/p>\n In conclusion, NF\u2011\u03baB is a central regulator of immunity and inflammation, and its dysregulation drives diverse diseases, making it an attractive therapeutic target. However, precise modulation is essential to balance efficacy<\/a> with preservation of normal physiology. Future research must bridge preclinical insights with clinical safety and efficacy in diverse patient populations.<\/p>\n Source:<\/p>\n Journal reference:<\/p>\n