Dysregulation of immune regulator NF-κB drives major human diseases

The NF‑κB family is a master regulator of innate and adaptive immunity. Its aberrant activation-via canonical or non‑canonical pathways-drives chronic inflammation, autoimmunity, allergies, and primary immunodeficiencies/autoinflammatory syndromes. This review synthesizes the molecular architecture, ubiquitin‑based relay systems, and dynamic regulation of NF‑κB, highlighting its dual pathways, roles in immune responses, cell survival, and development. NF‑κB integrates diverse signals for both acute and long‑term 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.

Introduction

NF‑κB controls genes involved in inflammation, immunity, cell survival, and proliferation. Triggered by cytokines (TNF‑α, IL‑1β), microbial products, or cellular stress, it translocates to the nucleus and induces pro‑inflammatory mediators. Acute activation clears pathogens and promotes tissue repair; chronic activation contributes to rheumatoid arthritis, inflammatory bowel disease (IBD), atherosclerosis, and cancer. NF‑κB also supports immune cell development and tolerance, and defects in its signaling cause immunodeficiency or autoimmunity. The family comprises five proteins-RelA (p65), c‑Rel, RelB, p50, and p52-all sharing a conserved Rel homology domain. RelA, c‑Rel, and RelB possess transactivation domains, while p50/p52 act as repressors; the predominant dimer is p50:RelA.

NF‑κB signaling: Canonical and non‑canonical pathways

Under resting conditions, IκB proteins (IκBα, IκBβ, IκBε) sequester NF‑κB in the cytoplasm. Upon stimulation, the IKK complex (IKKα, IKKβ, and NEMO) is activated; IKKβ phosphorylates IκBα, leading to its ubiquitination and proteasomal degradation. This frees NF‑κB for nuclear translocation, where it induces genes for inflammation (TNF‑α, IL‑6, COX‑2), survival (Bcl‑2, IAPs), and proliferation (cyclin D1). A negative feedback loop via IκBα synthesis terminates the response.

The canonical pathway is triggered by TNF‑α, IL‑1, Toll‑like receptors, and antigens; it relies on IKKβ/NEMO and IκBα degradation, releasing p50:RelA dimers rapidly and transiently. It is involved in chronic inflammation, autoimmunity, and cancer. The non‑canonical pathway is activated by BAFF‑R, CD40, and LTβR; it depends on NIK and IKKα to process p100→p52, releasing p52:RelB dimers slowly and sustainably. This pathway is critical for B‑cell maturation, lymphoid organogenesis, and tolerance, and its dysregulation is linked to autoimmunity and lymphoma.

Ubiquitin‑mediated relays are central to both pathways. K63‑linked 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.

Dysregulation in immunological diseases

In autoimmune diseases, NF‑κB 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‑23/IL‑17 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‑onset Behçet‑like autoinflammation.

Emerging research also links NF‑κB 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‑γ mutations, and an immunosuppressive tumor microenvironment. NF‑κB crosstalks extensively with JAK‑STAT, MAPK, PI3K‑AKT, Wnt/β‑catenin, and Notch pathways, diversifying outcomes and potentially causing resistance to single‑agent therapies.

Therapeutic strategies and biomarkers

Approved indirect strategies include anti‑cytokine biologics (anti‑TNF, anti‑IL‑1, anti‑IL‑6), BTK inhibitors, and proteasome inhibitors (bortezomib) that block IκB degradation. Emerging direct strategies target IKKβ/NEMO (potent but toxic, requiring tissue‑targeted delivery), NIK (for non‑canonical pathway), MALT1 (for lymphocyte‑driven 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.

Biomarkers and translational readouts include tissue assays (nuclear p65, phospho‑IκB/IKK, RelB/p52 localization), molecular signatures from gene expression profiling, and functional dynamics techniques (live‑cell imaging, single‑cell multi‑omics, mathematical modeling) that capture temporal patterns of NF‑κB activity. These tools aid diagnosis, prognosis, and patient selection for targeted therapies.

Future directions and conclusion

Emerging concepts include dynamics‑guided precision therapy, ubiquitin code editing, spatial immunology, tissue‑targeted delivery, genotype‑to‑therapy approaches, and combination logic to co‑target multiple nodes. This review moves beyond linear signaling to embrace a dynamic, precision‑targetable network. Limitations include insufficient experimental validation for emerging approaches, unresolved toxicity and specificity issues, and limited clinical biomarker validation.

In conclusion, NF‑κB 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 with preservation of normal physiology. Future research must bridge preclinical insights with clinical safety and efficacy in diverse patient populations.