nuclear factor kappa B
nuclear factor kappa B
Overview
Nuclear factor kappa B (NF-κB) is a family of pleiotropic transcription factors that serve as master regulators of inflammatory, immune, and cell survival responses across virtually all mammalian cell types. The NF-κB family comprises five members — RelA (p65), RelB, c-Rel, p50, and p52 — which form homo- or heterodimeric complexes that, in their inactive state, are sequestered in the cytoplasm by inhibitory proteins known as IκB (inhibitor of κB). Canonical NF-κB activation is triggered by a wide range of stimuli including pathogen-associated molecular patterns, proinflammatory cytokines such as Tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), oxidative stress, and receptor signaling. Upon activation, the IκB kinase (IKK) complex phosphorylates IκBα, targeting it for proteasomal degradation and releasing the NF-κB dimer to translocate to the nucleus, where it drives transcription of genes encoding cytokines, adhesion molecules, anti-apoptotic factors, and other inflammatory mediators. A non-canonical (alternative) pathway additionally exists, relying on IKKα-mediated processing of p100 to p52, and is implicated in lymphoid organogenesis and specific immune contexts.
The biological significance of NF-κB is underscored by its convergence with virtually every major signaling network in human disease. It cross-talks extensively with the MAPK cascade, the PI3K/Akt signaling pathway, the JAK-STAT axis, the NLRP3 inflammasome, toll-like receptor (TLR) signaling, and the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway. Dysregulated NF-κB activity has been mechanistically implicated in a broad spectrum of conditions spanning chronic inflammatory disorders, neurodegeneration, autoimmunity, metabolic disease, and cancer. This centrality makes NF-κB one of the most intensively studied signaling nodes in biomedical research, serving simultaneously as a mechanistic readout of disease pathology and as a high-priority therapeutic target.
Focus of Latest Publications
Recent publications consistently positioned NF-κB as a central inflammatory and stress-response node across diverse disease models. In gastric inflammation driven by Helicobacter pylori, NF-κB was examined alongside p38-MAPK, ERK1/2, and JNK as part of inflammatory signaling downstream of LOX-1. In diabetes-related studies, NF-κB suppression was reported in the context of honokiol-loaded solid lipid nanoparticles in STZ-induced type 1 diabetes, where reduced NF-κB signaling accompanied antioxidant effects and decreased apoptosis. A separate study in type 2 diabetic nephropathy compared NF-κB expression with PXDN as a potential diagnostic biomarker, highlighting its association with oxidative stress and renal injury.
NF-κB also appeared repeatedly in neuroinflammation and neuroprotection research. In amyloid-β-induced Alzheimer’s disease models, hippocampal NF-κB expression was measured by real-time PCR, and multiple interventions were reported to reduce NF-κB-associated inflammatory signaling, including abscisic acid, lawsone, myrtenol, loganic acid, and electroacupuncture via the SIRT1-NF-κB axis. In spinal cord injury and neuropathic pain models, indole-3-propionic acid, herkinorin, and IL-6R-CD3-engineered regulatory T cells were associated with suppression of NF-κB and related MAPK signaling, suggesting attenuation of astrocyte and microglial activation. carboplatin was also reported to inhibit NF-κB phosphorylation in TDP-43-transfected astrocytes, reducing pro-inflammatory cytokine production.
In gastrointestinal, hepatic, and metabolic inflammation, NF-κB was repeatedly identified as a mechanistic target. Quinoa bran polysaccharides, Melissa officinalis extract, naringin, mulberry leaf extracts, chestnut wood extract, and coffee pulp extract were all linked to inhibition of NF-κB signaling in colitis, reflux esophagitis, autoimmune hepatitis, non-alcoholic fatty liver disease, and intestinal oxidative stress models. In diabetic liver injury, TNF-α was reported to promote pyroptosis through the HMGB1/TLR4/MyD88/NF-κB pathway. In diabetic foot ulcer, NF-κB pathway enrichment was associated with disease progression, while in diabetic wound management, glabridin-containing eutectogel was reported to inhibit NF-κB and promote macrophage polarization from M1 to M2.
NF-κB was also central in musculoskeletal and bone-related pathology. In aging-related periodontitis, fibroblast activation protein triggered NF-κB signaling in senescent gingival fibroblasts, driving osteoclastogenesis and inflammatory bone resorption. curcumin attenuated hindlimb unloading-induced bone loss by suppressing NF-κB-mediated osteoclast activation, and molybdenum nanodots were reported to reprogram inflammatory osteolysis by curbing NF-κB-mediated M1 macrophage polarization. In intervertebral disc degeneration, aucubin and tanshinol were reported to inhibit NF-κB activation in nucleus pulposus cells.
Several studies linked NF-κB to macrophage polarization and innate immune remodeling. High-salt diet was described as activating NF-κB and NLRP3 signaling in macrophage-associated metabolic disorders, promoting a proinflammatory M1 phenotype. IL-4 was reported to facilitate M2 polarization through the NF-κB/IκB pathway in polycystic ovary syndrome. In coronary artery disease, the FVIIa/TF coagulation complex and PAR2 were shown to activate NF-κB in monocytes, aggravating inflammation. In allergic rhinitis, rosacea, and radiation pneumonitis, NF-κB suppression was repeatedly associated with reduced inflammatory mediator release and improved tissue outcomes.
Cancer-related studies also highlighted NF-κB as a pro-survival and immunomodulatory pathway. In colorectal cancer, EFHD2-driven lactate was reported to activate NF-κB signaling, contributing to immunosuppression and radioresistance. Another colorectal cancer study suggested that an 8-sulfonamidoquinoline compound may inhibit NF-κB by binding p65. In lung adenocarcinoma, an SLC2A1-associated malignant epithelial cell state was characterized by NF-κB activation and an immunosuppressive tumor microenvironment. In invasive lobular carcinoma, LOX inhibition downregulated NF-κB transcriptional programs, and in gastric cancer, chiral bismuth molybdate nanoparticles activated NF-κB in splenic macrophages as part of an immune-stimulatory mechanism.
Across these studies, NF-κB was most often treated as a downstream readout of inflammatory activation or as a therapeutic target for pathway inhibition. The recurring pattern was that interventions with plant-derived compounds, probiotics, nanoparticles, electroacupuncture, and engineered biologics reduced NF-κB phosphorylation, nuclear translocation, or expression of NF-κB-associated inflammatory mediators such as TNF-α, IL-1β, IL-6, iNOS, COX-2, and NLRP3. In some settings, however, NF-κB activation was intentionally leveraged to stimulate immune responses, as in dendritic cell hyperactivation and macrophage-mediated antitumor effects.