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NF-κB

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a family of ubiquitously expressed transcription factors that regulate the expression of genes involved in , immunity, survival, proliferation, and . The family consists of five structurally related proteins—RelA (p65), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52)—which form various homo- and heterodimers through their Rel homology domain to bind κB enhancer sequences in target gene promoters. Originally discovered in 1986 by Ranjan Sen and as a DNA-binding factor in the nuclei of mature B lymphocytes interacting with the immunoglobulin κ light chain enhancer, NF-κB has since been recognized as a master regulator of diverse cellular processes across multiple types.90347-6) NF-κB activation occurs primarily through two signaling pathways: the canonical pathway, which is rapidly induced by stimuli such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), (LPS), and receptors, leading to the and of inhibitory IκB proteins by the IKK complex (comprising IKKα, IKKβ, and NEMO), thereby allowing p50/ or p50/c-Rel dimers to translocate to the ; and the non-canonical pathway, which is slower and involves the processing of p100 to p52 by and IKKα in response to signals from receptors like CD40, , and LTβR, resulting in p52/RelB dimer nuclear entry. These pathways enable NF-κB to orchestrate innate and adaptive immune responses, including production (e.g., TNF-α, IL-6), T cell differentiation (e.g., Th1 and Th17 cells), and maturation, while also controlling activity and stress responses. Dysregulation of NF-κB signaling contributes to a wide array of pathological conditions, acting as a "double-edged sword" by promoting protective in but driving chronic diseases when aberrantly activated. In cancer, constitutive NF-κB activity supports tumor cell survival, proliferation, and resistance to and , as seen in , , and lymphoid malignancies. It also underlies autoimmune and inflammatory disorders such as , , and through excessive pro-inflammatory gene induction, and has been linked to metabolic syndromes and neurodegeneration via sustained inflammatory signaling. Ongoing research focuses on NF-κB inhibitors, including IKKβ blockers and natural compounds like aspirin, for therapeutic targeting in these diseases, highlighting its translational potential.

Introduction

Overview

NF-κB is a family of transcription factors composed of homo- or heterodimeric protein complexes that bind to specific DNA sequences known as κB sites to regulate the transcription of target genes. These factors primarily control the expression of genes involved in , immunity, cell survival, proliferation, and . First identified in 1986 as a nuclear factor binding to enhancer elements in B cells, NF-κB has since been recognized as a central regulator of inducible . Its activation is triggered by diverse stimuli, including proinflammatory cytokines such as TNF-α and IL-1, pathogen-associated molecular patterns like (LPS), , and environmental factors such as UV radiation. NF-κB plays a pivotal role in orchestrating innate and adaptive immune responses by coordinating the activity of immune and promoting inflammatory . However, dysregulation of NF-κB signaling contributes to pathological conditions, including cancer—where it promotes tumor and proliferation—and autoimmune diseases, where excessive activation drives chronic inflammation.

Discovery

NF-κB was first identified in 1986 by Ranjan and during investigations into the regulation of the immunoglobulin κ light chain gene enhancer in activated B lymphocytes. Their work focused on understanding how B-cell activation leads to enhanced transcription of immunoglobulin genes, revealing a specific DNA-binding activity in extracts from mature B cells. A pivotal experiment employed DNase I assays, which demonstrated that a factor protects a 10-base-pair sequence, termed the κB site (5'-GGGACTTTCC-3'), within the enhancer region from DNase digestion. Subsequent electrophoretic mobility shift assays confirmed this factor's sequence-specific binding. In a follow-up study, and showed that the κB-binding protein, named NF-κB, is inducible in non-B cells such as cells treated with phorbol esters, occurring via a posttranslational that releases NF-κB from cytoplasmic . Early characterizations indicated rapid translocation upon B-cell stimulation with or phorbol myristate acetate, with the active form appearing as a heterodimeric complex of 50-65 kDa subunits. Further milestones in the late 1980s linked NF-κB to the rel family. In 1990, studies demonstrated that the product of the cellular proto- c-rel forms an NF-κB-like complex that binds κB sites, while the viral v-rel oncoprotein suppresses such transcription, suggesting a role in lymphoid transformation. efforts advanced in 1990 with the of the encoding the p50 DNA-binding subunit of NF-κB, revealing its to the rel product and establishing NF-κB as part of a multi-subunit family. By the early 1990s, additional subunits including p65 (), c-Rel, RelB, and p52 were cloned and characterized, confirming the Rel/NF-κB family as comprising five related proteins capable of forming various homo- and heterodimers.

Structure and Composition

Protein Architecture

The NF-κB family of transcription factors shares a conserved N-terminal Rel homology domain (RHD), approximately 300 amino acids in length, which serves as the core architectural feature enabling their DNA-binding, dimerization, and nuclear translocation functions. The RHD comprises two immunoglobulin-like subdomains: the N-terminal DNA-binding domain (DBD, also called the N-terminal domain or NTD, spanning about 160–210 amino acids) and the C-terminal dimerization domain (DD, also called the C-terminal domain or CTD, about 100 amino acids), connected by a flexible linker of roughly 10 amino acids. The DBD recognizes and binds to specific κB DNA sites with the consensus sequence 5'-GGGRNNYYCC-3' (where R denotes purine, Y pyrimidine, and N any nucleotide), inserting loops into the major groove to contact bases while also interacting with the DNA phosphate backbone. The DD facilitates homo- or heterodimerization among family members, stabilizing the complex on DNA, and includes flexible loops that make additional nonspecific contacts with the DNA backbone. Embedded within the RHD, particularly in its C-terminal flexible region, is a nuclear localization signal (NLS) that directs the translocation of NF-κB dimers into the upon . In the cytoplasmic inactive state, this NLS is masked by inhibitory IκB proteins, which prevent nuclear import and DNA binding. IκB family members, such as , IκBβ, and IκBε, feature an inhibitory domain composed of 5–7 repeats—each consisting of an outer , an inner , and a β-hairpin—that form an elongated, curved structure. These repeats bind to the RHD's and the NLS region, locking NF-κB in a closed conformation that occludes the DNA-binding surface and adopts a helical structure over the NLS. C-terminal to the RHD in certain NF-κB subunits, a (TAD) is present in RelA (p65), c-Rel, and RelB, but notably absent in the processed forms p50 and p52, which derive from larger precursors. The TAD, typically unstructured and rich in acidic residues, recruits co-activators, chromatin-modifying enzymes, and the basal transcription machinery to enhance target . Structural insights into NF-κB architecture have been provided by X-ray crystallography, notably the 2.9 Å resolution structure of the RelA-p50 heterodimer bound to a κB DNA site from the immunoglobulin light-chain enhancer (PDB: 1LE5). This complex reveals how the DBD of each subunit engages a half-site (p50 recognizes a 5 bp half-site, RelA a 4 bp half-site), inducing a significant bend in the DNA (approximately 82°) to facilitate dimer contacts and enhance binding affinity. Additional structures, such as the RelA-p50-IκBα ternary complex (PDB: 1NFI), illustrate the inhibitory mechanism, with IκBα's ankyrin repeats occupying the DNA-binding interface and stabilizing the NLS in a helical form.

Family Members and Dimers

The NF-κB family consists of five structurally related transcription factors in mammals: RelA (also known as p65), RelB, c-Rel, NF-κB1 (p105/p50), and NF-κB2 (p100/p52). These proteins share a conserved Rel domain (RHD) that mediates DNA binding, dimerization, and nuclear localization, but differ in their C-terminal regions, which determine potential. NF-κB1 and NF-κB2 are synthesized as large precursor proteins, p105 and p100, respectively, which undergo post-translational to generate the mature subunits p50 and p52. This involves ubiquitin-mediated proteasomal , where p105 is constitutively cleaved to produce p50, while p100 to p52 is stimulus-induced and regulated by the IKKα . Notably, p50 and p52 lack transactivation domains (TADs), rendering them unable to activate transcription on their own unless partnered with TAD-containing Rel proteins. Functional NF-κB complexes form as homo- or heterodimers among these five members, with over a dozen possible combinations exhibiting distinct DNA-binding affinities and transcriptional activities. The most prevalent and well-characterized dimer is the p50/RelA (p65) heterodimer, which drives pro-inflammatory through the pathway. In contrast, the p52/RelB heterodimer predominates in the non- pathway and is essential for lymphoid and function. The p50/c-Rel dimer supports B-cell survival and proliferation, particularly in mature B cells where it is constitutively active. Dimer-specific diversity arises from the presence or absence of TADs: , RelB, and c-Rel possess TADs that enable transcriptional , while p50 and p52 do not, leading to inhibitory effects in homodimers like p50/p50, which bind DNA but repress transcription by competing with activating dimers. (p65) homodimers occur but are rare compared to the abundant p50/ heterodimer. Expression patterns further contribute to functional specificity; for instance, RelB is prominently expressed in dendritic cells, where it modulates immune responses.

Evolutionary Aspects

Species Distribution

NF-κB transcription factors and their homologs are widely distributed across the eukaryotic , with presence confirmed in mammals, , , and various , but notably absent in and . In mammals, including humans and mice, the full complement of five NF-κB family members—RelA (p65), RelB, c-Rel, NF-κB1 (p50/p105), and NF-κB2 (p52/p100)—is present and functional in immune and stress responses. possess four of these members (RelA/p65, c-Rel, p50/p105, and p52/p100), while exhibit three (RelA/p65, c-Rel, and p50/p105), indicating a progressive expansion of the family during vertebrate evolution. Among , homologs are evident in arthropods such as , where serves as a Rel family homolog, alongside Dif and Relish, which collectively regulate innate immune functions. However, nematodes like lack canonical NF-κB homologs, with their genome encoding only IκB-like inhibitors but no Rel homology domain (RHD)-containing transcription factors, resulting in a limited direct role for NF-κB signaling in immunity. In , true NF-κB orthologs are absent, though NPR1 functions as a structural and functional analog, resembling mammalian IκB proteins and coordinating salicylic acid-mediated defense responses akin to NF-κB pathways in animals. Sequence conservation of NF-κB components varies by domain and taxon, with the RHD—responsible for DNA binding, dimerization, and nuclear localization—showing high similarity exceeding 70% across vertebrates, enabling shared regulatory mechanisms. The transcription activation domain (TAD), in contrast, exhibits lower conservation, reflecting species-specific adaptations in target gene activation. In insects, the RHD of Dorsal displays approximately 40% identity to mammalian counterparts, sufficient for analogous roles in immunity. For instance, in Drosophila, the Toll signaling pathway activates Dorsal translocation to induce antimicrobial peptide genes, such as drosomycin, in response to fungal infections. Between model organisms, human and mouse NF-κB1 (p50/p105) and RelA (p65) share nearly identical sequences, with RHD similarity around 90%, which facilitates the translation of knockout studies from mice to human biology. Mouse models with targeted disruptions in these genes have been instrumental in elucidating NF-κB functions, as their pathways mirror human responses in inflammation and immunity due to this close homology.

Evolutionary Conservation

The NF-κB family emerged approximately 1 billion years ago in the last common ancestor of , marking a pivotal development in the of innate immunity. This timing aligns with the increasing complexity of multicellular life and the need for robust defense mechanisms against environmental stressors and pathogens. Phylogenetic studies indicate that ancestral NF-κB proteins were present in basal metazoans, with homologs identified in diverse lineages, underscoring its ancient role in coordinating immune responses. The Rel homology domain (RHD), central to DNA binding and dimerization, demonstrates remarkable conservation across metazoans, from sponges (Porifera) to humans, reflecting strong selective pressure to maintain its function in . In vertebrates, the RHD shares over 90% sequence identity among members, enabling conserved interactions with κB sites and upstream regulators. Notably, the p100/p52 branch of the NF-κB , characterized by C-terminal repeats for processing into active p52, arose specifically in vertebrates, expanding the repertoire of dimeric complexes for specialized immune signaling. Phylogenetic analyses further group NF-κB proteins by taxonomic clades, highlighting structural stability post-speciation while revealing lineage-specific adaptations. Gene duplications have been a key driver of NF-κB family diversification, allowing adaptation to increasingly complex immune demands in higher organisms, with extensive expansions leading to thousands of identified instances across species, particularly for c-Rel. This expansion facilitated the evolution of vertebrate-specific members like RelA/p65, enhancing responses to and . An illustrative case is the rel , derived from retroviral integration of the cellular c-rel gene in species, which exemplifies how such events can propagate and alter NF-κB function, contributing to oncogenic potential. Recent post-2020 studies have extended these insights, confirming NF-κB presence and activity in cnidarians for immune-related processes, including stress responses akin to , while documenting its loss in certain parasitic protists, likely due to simplified lifestyles reducing the need for elaborate immunity.

Signaling Pathways

Canonical Pathway

The canonical NF-κB pathway represents the primary mechanism for rapid NF-κB activation in response to pro-inflammatory stimuli, leading to the inducible degradation of inhibitory IκB proteins and subsequent nuclear translocation of NF-κB dimers. This pathway is triggered when ligands such as tumor necrosis factor-alpha (TNF-α) or interleukin-1 (IL-1) bind to their respective cell surface receptors, including the TNF receptor (TNFR1) or IL-1 receptor (IL-1R). Receptor engagement recruits adaptor proteins, such as TRADD and TRAF2 for TNFR1, which initiate a kinase cascade converging on the IκB kinase (IKK) complex. The IKK complex, composed of the catalytic subunits IKKα and IKKβ along with the regulatory subunit NEMO (also known as IKKγ), is activated through upstream s like TAK1, which IKKβ at key activation sites.81422-1) IKKβ, the predominant in this pathway, then the inhibitory protein IκBα at serine residues 32 and 36 (Ser32/Ser36). This event creates a recognition motif for the E3 SCF-βTrCP, which attaches Lys48-linked polyubiquitin chains to . The ubiquitinated is subsequently recognized and degraded by the 26S , thereby releasing the sequestered NF-κB dimer, typically the p50/ (p65) heterodimer, from its cytoplasmic retention. Upon liberation, the p50/RelA dimer translocates to the , where it binds to specific κB enhancer sites in the DNA, typically with the GGGRNNYYCC. This binding recruits coactivators such as the histone acetyltransferases CBP and p300, which acetylate s and NF-κB itself to facilitate transcriptional of genes. The pathway's is transient, typically lasting 30-60 minutes, due to a loop wherein NF-κB induces the transcription and rapid resynthesis of IκBα, which resequesters the dimer in the cytoplasm. This feedback mechanism ensures precise temporal control of the inflammatory response.

Non-canonical Pathway

The non-canonical pathway represents an alternative route for NF-κB activation, distinct from the rapid inflammatory responses mediated by the canonical pathway, and is primarily involved in processes such as lymphoid organogenesis and B-cell maturation. This pathway is triggered by specific stimuli, including lymphotoxin-β (LTβ) signaling through LTβ receptor, B-cell activating factor (BAFF) via BAFF receptor, and CD40 ligand (CD40L) engaging CD40, which are crucial for B-cell development and survival. These ligands induce receptor trimerization, recruiting adaptor proteins that initiate downstream signaling without involving the classical IKK complex. A pivotal event in this pathway is the stabilization of NF-κB-inducing kinase (NIK), which is normally targeted for proteasomal degradation by a complex involving TRAF3, TRAF2, and cIAPs. Upon ligand binding, TRAF3 undergoes K63-linked ubiquitination and degradation, thereby preventing NIK ubiquitination and degradation, allowing accumulation. Stabilized then phosphorylates and activates IKKα homodimers, independent of IKKβ or NEMO. Activated IKKα associates with p100 and phosphorylates it at serine residues 866, 870, and 872 in the C-terminal region, creating a phosphodegron motif recognized by the E3 β-TrCP. This leads to partial K48-linked polyubiquitination of p100, primarily at 856, which targets the C-terminal repeat domain for proteasomal processing while sparing the N-terminal Rel homology domain. The resulting generates the mature p52 subunit from p100, which remains bound to RelB to form the p52/RelB heterodimer. This dimer translocates to the , where it binds to κB sites in the promoters of target genes such as BAFF-R and , promoting B-cell survival and function. The non- pathway exhibits tissue specificity, being predominantly active in lymphoid organs like and lymph nodes, where it supports adaptive immune responses. Unlike the pathway's rapid within minutes, this route has a slower onset, typically requiring several hours for p52/RelB accumulation due to the time-intensive processing of p100.

and

The activation of NF-κB is finely tuned by various post-translational modifications that enhance its transcriptional activity. For instance, acetylation of the RelA subunit at lysine 310 by the histone acetyltransferase PCAF promotes the recruitment of co-activators and boosts NF-κB-dependent . Other modifications, such as of RelA at serine 276 by or IKKα, further stabilize its interaction with promoters and amplify potential. Inhibition of NF-κB signaling is primarily mediated by the IκB family of proteins, which includes classical members like , IκBβ, IκBε, and IκBζ that sequester NF-κB dimers in the and mask their nuclear localization signals. Atypical inhibitors, such as IκBNS, function predominantly in the nucleus to suppress NF-κB transcriptional activity by competing for DNA-binding sites or recruiting co-repressors. Physiological regulators like protein phosphatase 2A (PP2A) also play a key role by dephosphorylating IKK subunits, thereby attenuating activity and preventing sustained NF-κB . NF-κB signaling integrates with other pathways through extensive cross-talk, enabling context-specific responses. The MAPK pathways, including JNK and p38, intersect with NF-κB by phosphorylating IKK or , often amplifying inflammatory outputs in immune s. Similarly, the PI3K/Akt pathway enhances NF-κB via Akt-mediated of IKKα at 23, which activates the complex and promotes survival signals. In the nucleus, NF-κB activity is further modulated by co-repressors and compartmentalization. deacetylases (HDACs), such as and HDAC2, interact directly with the subunit to repress target gene transcription by maintaining in a condensed state. Additionally, sequestration of NF-κB into promyelocytic (PML) nuclear bodies limits its access to promoters, providing a mechanism for signal termination and prevention of excessive activation. Recent studies highlight the role of non-coding RNAs in establishing feedback loops that regulate NF-κB. For example, miR-146a, induced by NF-κB in response to inflammatory stimuli, targets IRAK1 and TRAF6 to dampen downstream signaling, forming a circuit that curbs prolonged ; this mechanism has been implicated in resolving acute responses in various cell types as of 2023.

Downstream Effects

Upon activation, NF-κB translocates to the and binds to κB sites in the promoters or enhancers of over 200 target genes, regulating a diverse array of cellular processes. Key targets include pro-inflammatory cytokines such as IL-6 and TNF-α, which amplify immune responses; adhesion molecules like , facilitating leukocyte recruitment; anti-apoptotic factors including and IAPs (e.g., cIAP1/2), which promote cell survival; and cell cycle regulators such as , driving proliferation. These genes are transcribed following NF-κB dimer binding to κB motifs, with binding affinity varying based on sequence variations; for instance, the high-affinity site GGGACTTTCC exhibits strong interaction with (p65)-containing dimers. The downstream effects of NF-κB activation are multifaceted, promoting cell survival by inhibiting pro-apoptotic pathways, such as caspase-8 activation through upregulation of and IAPs; enhancing via induction of c-Myc and ; and driving by increasing expression of COX-2 and iNOS, which contribute to and production, respectively. These outcomes enable rapid adaptation to stress signals but are tightly controlled to prevent excessive responses. The nature of these effects is highly context-dependent, influenced by the specific NF-κB dimer and co-factors. For example, p65 (RelA)/p50 heterodimers typically activate pro-survival and inflammatory genes, whereas p50 homodimers may repress transcription in the absence of co-activators, leading to anti-apoptotic or pro-apoptotic shifts depending on cellular conditions. Additionally, NF-κB activation often exhibits pulsatile dynamics, with oscillatory nuclear-cytoplasmic shuttling that fine-tunes gene expression; in macrophages, these damped oscillations synchronize to stimuli like TNF-α, producing distinct transcriptional patterns for tailored inflammatory responses.

Physiological Roles

In Immunity and Inflammation

NF-κB plays a pivotal role in innate immunity by orchestrating responses in macrophages and dendritic cells to -associated molecular patterns (PAMPs) recognized via Toll-like receptors (TLRs). Upon TLR engagement, such as TLR4 by (LPS), the canonical NF-κB pathway is activated, leading to the translocation of NF-κB dimers (primarily p65/p50) to the nucleus where they induce transcription of proinflammatory genes, including those encoding like and such as CXCL8 (IL-8), which recruit neutrophils to infection sites. This rapid activation ensures effective clearance and bridges innate and adaptive immunity by promoting . In adaptive immunity, NF-κB supports the survival, proliferation, and differentiation of T and B lymphocytes. In B cells, c-Rel-containing NF-κB complexes are essential for proliferation and survival signals from CD40 ligand, driving formation and production. Similarly, in T cells, NF-κB via receptors or costimulatory signals like enhances effector functions and memory cell development. A key function in B cells is facilitating class-switch recombination, where NF-κB, often in cooperation with non-canonical pathways, upregulates (AID) and cytokine-responsive elements to enable immunoglobulin isotype switching from IgM to IgG or IgA. NF-κB is central to inflammatory processes, where its activation coordinates production to resolve acute but can lead to sustained signaling in chronic conditions. mechanisms, such as the of the TNFAIP3 gene encoding A20, limit this response; A20 acts as a deubiquitinase to inhibit upstream signaling components like , preventing prolonged NF-κB activation and excessive . NF-κB integrates with and IRF pathways to fine-tune interferon responses during viral infections. Crosstalk between NF-κB and /7, often via shared promoters, enhances type I interferon production, while /2 activation downstream of interferons can reciprocally regulate NF-κB targets for balanced antiviral immunity. This synergy ensures coordinated innate responses without overactivation.

In Cellular Survival and Development

NF-κB plays a critical role in promoting cellular survival by suppressing apoptosis through the induction of anti-apoptotic genes, including Bcl-xL and c-FLIP, particularly in non-immune cells such as fibroblasts. This transcriptional regulation prevents programmed cell death in response to stressors like TNF-α, ensuring tissue integrity during homeostasis and development. In embryonic development, the RelA subunit of NF-κB is indispensable; RelA knockout mice exhibit embryonic lethality around day 15 due to widespread hepatic apoptosis triggered by unchecked TNF signaling, highlighting NF-κB's essential protective function. Beyond survival, NF-κB influences cell proliferation by driving the expression of cell cycle regulators, such as cyclin D1, which facilitates the G1/S phase transition in epithelial cells like keratinocytes. This mechanism supports controlled tissue renewal and repair without excessive growth. In developmental processes, the non-canonical NF-κB pathway is vital for organogenesis, particularly lymph node formation, where lymphotoxin-β receptor (LTβR) signaling activates the p52/RelB dimer to organize stromal cells and enable lymphoid structure assembly. Similarly, canonical NF-κB signaling contributes to limb development by regulating the apical ectodermal ridge in limb buds, where its inhibition leads to truncations and patterning defects; this involves crosstalk with BMP signaling to coordinate mesenchymal-epithelial interactions. NF-κB also modulates BMP-induced osteogenesis by interacting with Smad proteins, fine-tuning skeletal patterning. NF-κB maintains quiescence in the hematopoietic system, where basal activation via TRAF6-dependent signaling prevents premature and exhaustion of hematopoietic s, preserving long-term repopulation capacity. Furthermore, in epithelial tissues, NF-κB ensures barrier integrity and gut by coordinating antimicrobial responses and maintenance in intestinal epithelial cells, preventing microbial translocation while supporting symbiotic balance.

In the Nervous System

NF-κB is activated in neurons and within the by stimuli such as glutamate and growth factors, with translocation to the nucleus observed in dendritic compartments. In neurons, glutamate induces NF-κB through calpain-dependent , facilitating its role in synaptic and survival responses. This occurs rapidly following glutamate receptor stimulation, involving caspase-3-like proteases and leading to increased mobility of the p65 subunit in neurites. In , growth factors like (EGF) stimulate NF-κB to upregulate glutamate transporters such as GLT-1, supporting neuronal homeostasis via phosphatidylinositol 3-kinase-dependent pathways. (bFGF) similarly modulates astrocyte , indirectly influencing NF-κB signaling to attenuate reactive . In neuroprotective contexts, NF-κB promotes neuronal survival against ischemic injury by inducing manganese superoxide dismutase (MnSOD), an antioxidant enzyme that mitigates oxidative stress in hippocampal neurons. Activation of NF-κB, particularly via c-Rel-containing dimers, enhances expression of MnSOD and anti-apoptotic factors like Bcl-xL, conferring resilience to ischemia-reperfusion damage. This mechanism aligns with broader cellular survival pathways where NF-κB transcriptionally regulates protective genes in response to stress. For synaptic plasticity, NF-κB is essential for long-term potentiation (LTP) in the hippocampus, where its activation following synaptic stimulation supports structural remodeling and memory consolidation. NF-κB indirectly influences brain-derived neurotrophic factor (BDNF) expression, potentially via targets like XIAP, thereby facilitating BDNF-mediated enhancement of LTP and dendritic spine formation. During neural development, NF-κB contributes to astrogliogenesis by regulating progenitor differentiation in the and , where sustained activity in gliogenic progenitors inhibits fate and promotes astrocytic commitment. In the , NF-κB p50 subunit modulates astrocyte-mediated specification of neural precursors, favoring over gliogenesis and ensuring balanced neuronal populations. Additionally, constitutive NF-κB activity supports neuronal survival and process outgrowth in developing regions, including hippocampal neurons, by controlling elongation and arborization.

Pathological Implications

In Cancer

NF-κB plays a pivotal oncogenic role in cancer by promoting tumor cell survival, proliferation, metastasis, and resistance to therapies through its of pro-survival and inflammatory genes. Constitutive activation of NF-κB is a hallmark in various malignancies, often driven by genetic alterations that disrupt its normal regulation. For instance, oncogenic mutations leading to chronic activation of the IKKβ kinase in the pathway cause persistent and of IκB inhibitors, enabling sustained nuclear translocation of NF-κB subunits like p65/. This mechanism is particularly prevalent in B-cell lymphomas, where IKKβ activation sustains tumor growth by upregulating anti-apoptotic genes such as and XIAP. Additionally, mutations in negative regulators like TNFAIP3 (A20) contribute to this aberrant signaling, fostering a pro-tumorigenic environment. NF-κB engages in extensive cross-talk with other oncogenic pathways, amplifying its effects in cancer progression. In colorectal and breast cancers, NF-κB interacts with the Wnt/β-catenin pathway, where β-catenin stabilizes and enhances NF-κB DNA binding, promoting epithelial-mesenchymal transition (EMT) and metastasis. Similarly, in breast cancer, EGFR signaling activates NF-κB via IKK phosphorylation, driving downstream targets that support tumor invasion and survival. These interactions underscore NF-κB's role in integrating multiple signals to sustain malignancy. The pathological effects of NF-κB in cancer include enhanced tumor invasion and through upregulation of matrix metalloproteinases (MMPs) like MMP-9, which degrade to facilitate , and (VEGF), which recruits endothelial cells for . In solid tumors such as and colon cancers, as well as hematologic malignancies like , constitutive NF-κB activity is detected in a significant proportion of cases—up to 67% in colorectal cell lines and 82% in primary myeloma samples—and correlates with aggressive disease. Nuclear staining of p65 serves as a prognostic marker, with high levels indicating poor outcomes in patients, particularly in triple-negative subtypes. Furthermore, NF-κB confers chemoresistance by inducing ABC transporters such as MDR1/ABCB1, which efflux chemotherapeutic agents like , thereby protecting cancer cells from . In the therapeutic landscape, targeting NF-κB has shown promise in sensitizing tumors to . IKK inhibitors, including —a that indirectly blocks IκB degradation—have demonstrated efficacy in by reducing NF-κB activity and enhancing when combined with standard regimens. Recent studies highlight NF-κB's contribution to immunotherapy resistance, particularly through induction of PD-L1 expression via p65 binding to its promoter, which suppresses T-cell responses in non-small cell and other solid tumors; inhibiting this axis, as explored in 2023–2024 investigations, potentiates anti-PD-1/PD-L1 efficacy.

In Chronic Diseases

NF-κB plays a central role in the pathogenesis of various chronic diseases by sustaining inflammatory responses that contribute to tissue damage and immune dysregulation. In autoimmune conditions such as (RA) and (MS), aberrant NF-κB activation amplifies pro-inflammatory production, perpetuating disease progression. Similarly, in (IBD) and , NF-κB drives epithelial and , leading to barrier impairment and vascular pathology. Recent research also implicates persistent NF-κB signaling in post-viral syndromes like , where it underlies chronic fatigue through ongoing storms. Defective negative feedback mechanisms, such as A20 dysfunction, further exacerbate these risks by failing to restrain NF-κB activity. In , sustained NF-κB activation in synovial fibroblasts and immune cells is driven by (TNF) and interleukin-1 (IL-1), leading to the expression of pro-inflammatory mediators that erode joint tissues. This pathway upregulates cytokines like IL-6 and matrix metalloproteinases, fostering chronic and formation. NF-κB also targets IL-17 production by Th17 cells, which synergizes with TNF to enhance endothelial activation and leukocyte recruitment in the synovium, amplifying autoimmune inflammation. In , NF-κB is hyperactivated in T cells, , and within the , promoting demyelination through TNF and IL-1β secretion that disrupts the blood-brain barrier. This sustained signaling contributes to axonal damage and plaque formation, with RelA and c-Rel subunits specifically driving pathogenic CD4+ T cell differentiation. Inflammatory bowel disease, including , involves NF-κB activation in intestinal epithelial cells that impairs barrier integrity and exacerbates mucosal . Epithelial NF-κB, triggered by microbial signals via Toll-like receptors, induces the production of and adhesion molecules, leading to increased permeability and bacterial translocation that perpetuate . Studies show that inhibiting NF-κB in these cells is sufficient to resolve experimental by restoring proteins and reducing cytokine-driven . This dysregulation contrasts with physiological , where transient NF-κB activity maintains gut . In , NF-κB activation in endothelial cells at sites of disturbed blood flow promotes the expression of adhesion molecules such as vascular cell molecule-1 () and intercellular molecule-1 (), facilitating recruitment and plaque initiation. This pathway, primed by oxidized and , sustains chronic vascular inflammation and accumulation, advancing lesion progression to instability. Endothelial-specific NF-κB inhibition has been shown to attenuate plaque formation in mouse models, highlighting its causal role. Emerging evidence from 2025 links persistent NF-κB activation to chronic fatigue in , where unresolved signaling via and IFN-γ pathways maintains low-grade inflammation in affected individuals. This sustained activity, observed in peripheral blood mononuclear cells, correlates with symptoms resembling , driven by heightened innate immune responses post-SARS-CoV-2 infection. Feedback failure in NF-κB regulation, particularly through A20 (TNFAIP3) mutations or , heightens susceptibility to chronic inflammatory diseases by preventing deubiquitination and termination of signaling cascades. A20 normally inhibits TNF- and TLR-induced NF-κB to curb excessive release, but its deficiency leads to autoinflammatory phenotypes with increased risk for conditions like and IBD. Genetic variants in A20 are associated with disrupted immune , amplifying disease chronicity across multiple tissues.

Genetic Disorders (e.g., NEMO Deficiency)

NEMO (NF-κB essential modulator, also known as IKKγ) deficiency is a rare X-linked caused by hypomorphic mutations in the IKBKG , leading to impaired activation of the IKK complex and defective NF-κB signaling. These mutations, often missense or small deletions, result in reduced NEMO protein expression or function, disrupting NF-κB translocation to the nucleus in response to stimuli like TNF-α or TLR ligands, while sparing the non- pathway. The disorder manifests as X-linked with (EDA-ID), characterized by anhidrotic features such as sparse hair, missing or conical teeth, , and facial dysmorphism, alongside severe . Patients with NEMO deficiency typically present with recurrent and severe infections starting in infancy, including pyogenic bacterial infections (e.g., sepsis, ), opportunistic mycobacterial infections (e.g., *), and viral infections (e.g., herpesviruses like or CMV). Immunologic findings include (particularly low IgG and IgM), impaired antibody responses to vaccines, reduced memory B cells, and defective TLR-mediated production (e.g., diminished TNF-α and IL-12). contributes to additional complications like and chronic eczema, while the NF-κB defect predisposes to or in some variants. Without intervention, mortality is high, with up to 30% of cases succumbing to disseminated infections by . Diagnosis relies on genetic sequencing of the IKBKG gene to identify hypomorphic mutations, often complemented by functional assays such as NF-κB activation in response to stimuli or assessment of p65 () phosphorylation. for NEMO protein expression in leukocytes or analysis of IκBα degradation can confirm impaired signaling. Early molecular testing is crucial, as mutations account for most cases, though 5′ UTR variants may require extended sequencing. Management involves prophylactic antibiotics, intravenous immunoglobulin replacement, and aggressive treatment of infections; (HSCT) offers potential cure for the immunologic component, with a reported overall survival rate of 74% at a follow-up of 57 months across 29 patients, though ectodermal features persist post-transplant. Other monogenic NF-κB disorders include , an autosomal dominant cause of (CVID), resulting from heterozygous loss-of-function mutations in NFKB1 that reduce p50 protein levels and impair B-cell differentiation and antibody production. Affected individuals exhibit recurrent sinopulmonary infections, , (e.g., cytopenias), and increased risk, with diagnosis via and functional assays showing reduced NF-κB transcriptional activity.00284-0) RelA (RELA) mutations, particularly dominant-negative heterozygous variants, underlie a novel type I interferonopathy with autoinflammation and autoimmunity, featuring chronic mucocutaneous ulcers, periodic fever, inflammatory bowel disease, and hematologic autoimmunity due to enhanced type I IFN production from disrupted RelA function. Diagnosis involves whole-exome sequencing revealing truncating or missense mutations, confirmed by elevated interferon signatures in patient cells.

In Aging and Metabolic Disorders

NF-κB contributes to the process of inflammaging, characterized by low-grade chronic inflammation that accumulates with age and drives tissue dysfunction. In aging tissues such as adipose and brain, persistent NF-κB activation is triggered by (ROS) and the (SASP), where senescent cells release proinflammatory factors that sustain NF-κB signaling, exacerbating and age-related decline. In , NF-κB plays a central role in inflammation and . Tumor necrosis factor-α (TNF-α), produced by macrophages infiltrating , activates NF-κB in adipocytes, leading to upregulation of suppressor of signaling 3 (SOCS3), which inhibits insulin substrate-1 (IRS-1) and impairs insulin signaling. This mechanism links obesity-induced metaflammation to metabolic dysregulation, promoting and progression. NF-κB also contributes to metabolic disorders like and non-alcoholic (NAFLD). In , cytokine-induced NF-κB activation in pancreatic β-cells promotes by upregulating pro-death genes such as , reducing β-cell mass and insulin secretion. In NAFLD, NF-κB activation in Kupffer cells, the liver's resident macrophages, is driven by gut-derived (LPS) and lipid overload, resulting in production of TNF-α and interleukin-6 (IL-6), which foster hepatic and . Caloric restriction (CR) mitigates NF-κB-driven pathology in aging and metabolic disorders by enhancing (SIRT1) activity, which deacetylates the /p65 subunit of NF-κB at lysine 310, suppressing its transcriptional activity and reducing proinflammatory . This SIRT1-mediated inhibition helps preserve metabolic , as evidenced in models of and where CR attenuates and hepatic . Recent studies highlight NF-κB's role in , the age-related loss of mass. Inhibition of NF-κB signaling in muscle cells reduces and , preserving muscle mass and function; for instance, targeting NF-κB pathways has been shown to counteract muscle in aging models by suppressing expression and enhancing satellite cell activity.

Therapeutic Targeting

Pharmacological Inhibitors

Pharmacological inhibitors of NF-κB encompass a diverse array of synthetic and natural compounds designed to suppress its aberrant activation, which is implicated in inflammatory and neoplastic disorders. These agents primarily target key components of the NF-κB signaling pathway, such as the (IKK) complex, upstream activators like tumor necrosis factor-alpha (TNF-α), or downstream transcription factors, aiming to mitigate , promote , and enhance therapeutic responses in diseases like cancer and autoimmune conditions. Among synthetic inhibitors, those targeting the IKK complex have been prominent due to its central role in NF-κB activation. , a , indirectly blocks NF-κB by preventing the degradation of , thereby retaining NF-κB in the ; it is FDA-approved for , where it improves overall survival rates in combination regimens, with response rates exceeding 70% in frontline settings. However, bortezomib's efficacy is tempered by toxicity, including in up to 30% of patients, which has prompted development of less neurotoxic analogs like . Selective IKKβ inhibitors, such as IMD-0354, directly inhibit IKKβ phosphorylation of , demonstrating preclinical anti-inflammatory effects in models of and cancer by reducing NF-κB nuclear translocation. Despite promising potency, IMD-0354 and similar compounds face clinical challenges, including off-target effects on transport, limiting their advancement beyond phase I trials. Upstream inhibition of NF-κB activation via TNF-α blockade represents another established strategy, particularly in inflammatory diseases. Infliximab, a monoclonal anti-TNF-α antibody, neutralizes TNF-α to prevent IKK activation and subsequent NF-κB translocation, leading to reduced cytokine production; it is approved for rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), achieving clinical remission in 40-60% of RA patients and mucosal healing in up to 50% of Crohn's disease cases. While effective, infliximab's use is complicated by immunogenicity, with up to 40% of patients developing antibodies that diminish response, alongside increased infection risks such as tuberculosis reactivation. Natural compounds offer additional avenues for NF-κB inhibition with potentially lower toxicity profiles. Curcumin, derived from , suppresses NF-κB by directly inhibiting IKK activity and IκBα phosphorylation, as evidenced in preclinical models of and cancer where it reduced NF-κB-dependent . Similarly, , a from grapes, activates SIRT1 to deacetylate and inactivate the RelA/p65 subunit of NF-κB, attenuating TNF-α-induced activation in cellular assays and animal models of . These agents show synergistic potential with synthetic inhibitors but require improved for clinical translation. Recent advancements include targeted degradation strategies and subunit-specific inhibitors entering early clinical evaluation. Proteolysis-targeting chimeras (PROTACs) designed for /p65 degradation, such as PBD-based conjugates, selectively deplete in preclinical models, overcoming resistance to inhibitors like by promoting ubiquitin-mediated proteasomal breakdown without broad NF-κB suppression. Selective p65 inhibitors, including small molecules disrupting p65 dimerization, have shown promise in IBD models by reducing colonic inflammation. Overall, while 's approval in myeloma underscores NF-κB inhibition's therapeutic value, ongoing efforts address toxicity and selectivity to expand applications in RA and beyond.

Non-drug Interventions

Non-drug interventions for modulating NF-κB activity encompass modifications, dietary strategies, and emerging therapies that target its overactivation in inflammatory conditions without relying on synthetic pharmaceuticals. These approaches leverage natural mechanisms to inhibit NF-κB signaling pathways, such as the IKK complex, thereby reducing and associated pathologies. Dietary interventions rich in components have shown promise in suppressing NF-κB activation. Omega-3 fatty acids, particularly (EPA), inhibit IKK activity, preventing the and degradation of IκBα and subsequent NF-κB nuclear translocation in various cell types. This mechanism contributes to reduced inflammatory responses in conditions like metabolic . Similarly, adherence to the , characterized by high intake of fruits, vegetables, , and , lowers markers of inflammaging by downregulating NF-κB-dependent production and . Clinical studies indicate that this dietary pattern reduces circulating levels of pro-inflammatory mediators, such as IL-6 and CRP, through sustained modulation of NF-κB pathways. Regular physical activity, especially aerobic exercise, offers a preventive strategy by activating AMP-activated protein kinase (AMPK) in adipose tissue, which in turn suppresses NF-κB activity. Aerobic training enhances AMPK phosphorylation, leading to inhibition of the IKK-NF-κB axis and decreased expression of pro-inflammatory adipokines like TNF-α in obese individuals. This effect is particularly evident in metabolic syndrome models, where exercise reduces adipose inflammation and improves insulin sensitivity without pharmacological aid. Probiotic supplementation represents another non-drug approach, particularly for gut-related disorders like (IBD). Strains such as plantarum modulate to inhibit NF-κB signaling in intestinal epithelial cells, reducing pro-inflammatory release and alleviating symptoms in animal models. Recent research highlights evolving links between and NF-κB activation in ; for instance, lipopolysaccharide (LPS) from dysbiotic gut bacteria triggers TLR4-NF-κB pathways, exacerbating adipose inflammation, with 2024-2025 studies emphasizing probiotic restoration of microbial balance to mitigate these effects. Gene therapy using adeno-associated virus (AAV) vectors to deliver dominant-negative has demonstrated therapeutic potential in preclinical models. Intra-articular administration of AAV2 encoding a super-repressor form of (IκBα SR), which resists degradation and sequesters NF-κB in the , partially ameliorates and clinical scores in rat models of antigen-induced by blocking NF-κB translocation to the .

Challenges and Future Directions

The ubiquitous role of NF-κB in and cellular presents significant challenges for therapeutic targeting, as broad inhibition often leads to severe side effects such as and impaired . For instance, systemic inhibition of NF-κB pathways can disrupt essential anti-apoptotic and inflammatory responses, exacerbating vulnerability to infections and delaying tissue repair in non-cancerous contexts. Additionally, the context-dependent nature of NF-κB signaling complicates its inhibition in cancer, where it can promote tumor progression in some settings while exerting anti-tumor effects in others, such as enhancing immune surveillance. This duality raises concerns that pan-inhibitors may inadvertently foster malignant development in tissues reliant on NF-κB for protective functions. Achieving specificity remains a key hurdle, as most current inhibitors target the canonical pathway broadly, lacking selectivity for specific dimers like RelB:p52, which are implicated in non-canonical signaling and . Dimer-selective approaches, such as RelB-targeting small molecules, offer promise for mitigating chronic inflammation without widespread , but their development is limited by the complexity of NF-κB multidimer configurations. For example, enhancing p52 homodimer activity could selectively dampen autoimmune responses, yet distinguishing these from canonical dimers like RelA:p50 requires advanced biophysical characterization to avoid off-target effects. Strategies focused on autoimmune diseases highlight the need for pathway-specific modulation to balance efficacy and safety. Looking ahead, artificial intelligence-driven design of NF-κB inhibitors represents an emerging frontier, with machine learning models like NfκBin enabling high-throughput screening of TNF-α-induced pathway disruptors to identify novel, selective compounds. CRISPR-based editing of NFKB1 enhancers holds potential for precise regulation, as in vivo screens have linked NFKB1 variants to therapy resistance, suggesting targeted modifications could restore sensitivity in resistant tumors. Furthermore, investigating NF-κB's role in environmental stresses, such as heat shock, could inform therapies for climate-related health impacts, given its essential function in preventing stress-induced apoptosis and regulating response dynamics to temperature fluctuations. Recent advances in 2025 include single-cell RNA-seq studies unveiling NF-κB transcriptional heterogeneity within tumor microenvironments, which may guide personalized interventions, alongside its growing therapeutic potential in neurodegeneration through pathway modulation to curb neuroinflammation. Post-2023 multimodal therapies combining NF-κB inhibitors with immune checkpoint blockers have shown synergy in enhancing anti-tumor immunity, addressing resistance mechanisms in solid tumors.

References

  1. [1]
    NF-κB signaling in inflammation - Nature
    Jul 14, 2017 · The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses.
  2. [2]
    NF-κB in biology and targeted therapy: new insights and ... - Nature
    Mar 4, 2024 · In this review, we first scrutinize the research process of NF-κB ... The mammalian NF-κB transcription factor family consists of five members, ...
  3. [3]
    Structural studies of NF-κB signaling | Cell Research - Nature
    Dec 7, 2010 · In this review, structural discoveries in the NF-κB pathway are presented. ... NF-κB: the central transcription factor. DNA recognition by NF-κB.Introduction · Nemo: The Key Ikk Regulatory... · Trafs: Major Adaptor And...<|control11|><|separator|>
  4. [4]
    The NF-κB Family of Transcription Factors and Its Regulation - PMC
    Nuclear factor-κB (NF-κB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, ...
  5. [5]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC2742082
  6. [6]
    NF-κB in Oxidative Stress - PMC - NIH
    In this review, we focus on role of oxidative stress on different mediators of the NF-κB pathway, and the role of NF-κB activation in the modulation of ...Missing: radiation | Show results with:radiation
  7. [7]
    NF-kB as a key player in regulation of cellular radiation responses ...
    In this review we have considered activation of NF-κB as a potential marker in screening of radiation countermeasure agents (RCAs) and cellular radiation ...
  8. [8]
    NF‐κB signaling in inflammation and cancer - PMC - PubMed Central
    Since nuclear factor of κ‐light chain of enhancer‐activated B cells (NF‐κB) was discovered in 1986, extraordinary efforts have been made to understand the ...
  9. [9]
    NF-κB, an active player in human cancers - PMC - PubMed Central
    NF-κB activity not only promotes tumor cells proliferation, suppresses apoptosis, and attracts angiogenesis, but it also induces epithelialmesenchymal ...
  10. [10]
    NF-κB: At the Borders of Autoimmunity and Inflammation - PMC
    The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory response.
  11. [11]
    A Structural Guide to Proteins of the NF-κB Signaling Module - PMC
    Each of the subunits contains the Rel homology region (RHR) near its amino terminus. The RHR consists of two folded domains, the amino-terminal domain (NTD) and ...Missing: seminal | Show results with:seminal
  12. [12]
    Structural studies of NF-κB signaling - PMC - PubMed Central
    Dec 7, 2010 · NF-κB proteins activate target genes through a highly conserved DNA-binding/dimerization domain called the Rel homology region (RHR) (Figure 1A) ...Missing: seminal papers
  13. [13]
    Crystal structure of p50/p65 heterodimer of transcription factor NF ...
    Here we report the crystal structure at 2.9 A resolution of the p50/p65 heterodimer bound to the kappaB DNA of the intronic enhancer of the immunoglobulin ...
  14. [14]
    The Nfkb1 and Nfkb2 Proteins p105 and p100 Function as the Core ...
    Jun 12, 2009 · The Nfkb1 and Nfkb2 proteins, p105 and p100, have dual functions in the NF-κB signaling system. They are best known as precursors of p50 and p52 ...
  15. [15]
    The Many Roles of Ubiquitin in NF-κB Signaling - PMC - NIH
    Precursor proteins p105 and p100 also contain Ankyrin repeats at the C-terminus and can play the role, before processing to generate p50 and p52, of IκB-like ...
  16. [16]
    NF-κB in immunobiology - PMC - NIH
    NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system.Missing: 1986 | Show results with:1986
  17. [17]
    Principles of dimer-specific gene regulation revealed by a ...
    NF-κB represents homo- and heterodimers of five different family members: c-Rel (REL), RelA/p65 (RELA), RelB (RELB), p50/p105 (NFKB1), and p52/p100 (NFKB2).
  18. [18]
    The non-canonical NF-κB pathway in immunity and inflammation
    Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions.Non-Canonical Nf-κb... · Role In Immune Regulation · Role In Inflammatory...
  19. [19]
    Mechanism of κB DNA binding by Rel/NF-κB dimers
    In mammals, the Rel/NF-κB dimers arise from five polypeptides, p50, p52, p65, c-Rel, and RelB. The most abundant of these dimers are the p50/p65 heterodimer and ...Missing: rare | Show results with:rare
  20. [20]
    Transient interactions modulate the affinity of NF-κB transcription ...
    May 28, 2024 · Both RelA and p50 form stable homodimers although RelA is present mostly as p50:RelA heterodimer, which is the most abundant NF-κB in cell. The ...
  21. [21]
    NF-κB RelB suppresses the inflammatory gene expression ... - Nature
    Feb 11, 2025 · NF-κB RelB suppresses the inflammatory gene expression programs of dendritic cells by competing with RelA for binding to target gene promoters.
  22. [22]
    NF-κB Transcription Factors: Their Distribution, Family Expansion ...
    Sep 10, 2024 · The Nuclear Factor Kappa B (NF-κB) transcription factor family consists of five members: RelA (p65), RelB, c-Rel, p50 (p105/NF-κB1), and p52 (p100/NF-2.2. Some Nf-κb Proteins... · 2.3. Nf-κb Proteins... · 2.4. Relb And C-Rel Have The...
  23. [23]
    NF-κB/Rel Proteins and the Humoral Immune Responses of ...
    Nuclear Factor-κB (NF-κB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom.Nf-κb/rel Proteins And The... · 2.2 Peptidoglycan... · 4 Nf-κb Proteins
  24. [24]
    Evidence for the ancient origin of the NF-κB/IκB cascade - PNAS
    Unexpectedly, the canonical NF-κB signaling pathway is not functional in the immune system of Caenorhabditis elegans. Therefore, the ancient origin of the NF-κB ...
  25. [25]
    Mustard NPR1, a mammalian IkappaB homologue inhibits NF ...
    Dec 18, 2009 · IkappaB proteins possess ankyrin repeats for binding to and inhibiting NF-kappaB. The regulatory protein, NPR1 from Brassica juncea possesses ...Missing: analog | Show results with:analog
  26. [26]
    NF-κB in the Immune Response of Drosophila - PMC
    The Toll and Imd pathways stimulate antimicrobial responses to bacteria and fungi in Drosophila. Both act via NF-κB transcription factors. The paramount ...
  27. [27]
    Signaling to NF-κB - Genes & Development
    In this review, we provide an overview of established NF-κB signaling pathways with focus on the current state of research into the mechanisms that regulate ...Signaling Pathways To Nf-κb · Regulation Of Ikk · Acknowledgments<|control11|><|separator|>
  28. [28]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3083852/
  29. [29]
    NF-κB Transcription Factors: Their Distribution, Family Expansion ...
    Sep 10, 2024 · They all have a conserved N-terminal region, known as the Rel homology domain (RHD), which contains the subdomains DNA binding domain (RHD-DBD) ...Missing: seminal | Show results with:seminal
  30. [30]
    [PDF] Transcription factor NF-κB in a basal metazoan, the sponge, has ...
    Nov 15, 2019 · Our own phylogenetic comparison of RHD sequences confirmed that the Aq RHD is more similar across phyla to the RHDs of other NF-κB proteins as ...
  31. [31]
    NF-κB is essential for epithelial-mesenchymal transition and ... - JCI
    A link between aberrant NF-κB activity and cancer was initially suggested by the identification of v-Rel, a viral homolog of c-Rel, as the transforming oncogene ...
  32. [32]
    The IκB kinase complex in NF-κB regulation and beyond - PMC
    IκB phosphorylation leads to its ubiquitin-mediated proteasomal degradation, enabling NF-κB dimers translocation to the nucleus, where they bind to DNA and ...
  33. [33]
    NF-κB, the first quarter-century: remarkable progress and ...
    NF-κB proteins bind to κB sites as dimers, either homodimers or heterodimers, and can exert both positive and negative effects on target gene transcription.
  34. [34]
    https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-065x.2012.01096.x
  35. [35]
    https://www.mdpi.com/1422-0067/25/18/9793
  36. [36]
    Non-canonical NF-κB signaling pathway - PMC - PubMed Central
    Abstract. The non-canonical NF-κB pathway is an important arm of NF-κB signaling that predominantly targets activation of the p52/RelB NF-κB complex.
  37. [37]
    https://www.nature.com/articles/bjc2015410
  38. [38]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC4303448/
  39. [39]
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3278889/
  40. [40]
    Lost and Found: The Family of NF-κB Inhibitors Is Larger than ...
    Jun 16, 2023 · NF-κB signalling is largely controlled by the family of 'inhibitors of NF-κB' (IκB). The relevant databases indicate that the genome of ...
  41. [41]
    Identification of PP2A as a crucial regulator of the NF-κB feedback loop
    Jun 27, 2008 · Our data shed new light on the significance of negative feedback regulation of NF-κB and identifies PP2A as the key regulator of this process.
  42. [42]
    Akt-mediated regulation of NFκB and the essentialness of NFκB for ...
    Here we show that constitutively active Akt stimulates IKK activity by phosphorylation on T23 in the IKKα subunit. The IKK complex then phosphorylates both the ...
  43. [43]
    The p65 (RelA) subunit of NF-kappaB interacts with the histone ...
    The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression · Abstract.
  44. [44]
    Regulation of NF-κB by PML and PML-RARα | Scientific Reports
    Mar 20, 2017 · PML nuclear bodies form stable and transient interactions with a large number of proteins and play an important regulatory role in apoptosis, ...
  45. [45]
    MicroRNA-146a negatively regulates inflammation via the IRAK1 ...
    Jul 11, 2023 · Our present study shows a negative feedback regulation of miR-146a on NF-κB activation and its downstream secreted inflammatory cytokines via ...
  46. [46]
    NF-kB Target Genes » NF-kB Transcription Factors | Boston University
    For 135 additional potential NF-kB target genes, which are predicted by computer-based methods to have composite NF-kB/C/EBP regulatory sites, see Shelest et al ...
  47. [47]
    NF-κB oscillations translate into functionally related patterns of gene ...
    Jan 14, 2016 · NF-κB oscillations synchronize to external perturbations as a damped oscillator, producing different transcription dynamics.
  48. [48]
    Targeting NF-κB pathway for the therapy of diseases - Nature
    Sep 21, 2020 · NF-κB forms a family of transcription factors that play essential roles in multiple physiological and pathological processes. There are two ...
  49. [49]
    NF-κB in immunobiology | Cell Research - Nature
    Jan 18, 2011 · NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system.
  50. [50]
    NF-κB in inflammation and cancer | Cellular & Molecular Immunology
    Jun 25, 2025 · Dysregulated NF-κB activation contributes to acute and chronic inflammatory disorders, mostly through the aberrant induction of genes encoding ...
  51. [51]
    A20: linking a complex regulator of ubiquitylation to immunity and ...
    Oct 12, 2012 · TNFAIP3 polymorphisms and altered A20 expression have been correlated with therapeutic responses to TNF blockade in the treatment of rheumatoid ...Missing: sustained | Show results with:sustained
  52. [52]
    The role of SARS-CoV-2-mediated NF-κB activation in COVID-19 ...
    Oct 23, 2023 · We summarized the role of NF-κB activation during SARS-CoV-2 invasion and replication, particularly the angiotensin-converting enzyme 2 (ACE2)-mediated NF-κB ...Missing: post- | Show results with:post-
  53. [53]
    Prolonged immune activation in post-acute sequelae of SARS-CoV-2
    Sep 24, 2025 · Among these, Neu5 exhibited the highest enrichment for gene modules associated with lung fibrosis, TNF-α/NF-κB signaling, and inflammatory ...
  54. [54]
    Deep insight into cytokine storm: from pathogenesis to treatment
    Apr 16, 2025 · This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of ...
  55. [55]
    Cell fate in antiviral response arises in the crosstalk of IRF, NF-κB ...
    Feb 5, 2018 · We demonstrate that feedback interactions between the IRF3, NF-κB and STAT pathways lead to switch-like responses to a viral analogue, poly(I:C), in contrast ...
  56. [56]
    The multiple roles of interferon regulatory factor family in health and ...
    Oct 9, 2024 · This review primarily synthesizes the structural characteristics, post-translational modification sites, biological roles, and associated ...
  57. [57]
    PUMA is directly activated by NF-κB and contributes to TNF-α ...
    May 15, 2009 · The protection by NF-κB is due to transcriptional activation of a number of antiapoptotic proteins, such as c-FLIP, Bcl-2, Bcl-XL, cIAP2, and A ...Results · Tnf-α-Induced And... · Transfection And Reporter...Missing: lethal | Show results with:lethal
  58. [58]
    Absence of tumor necrosis factor rescues RelA-deficient mice from ...
    Mice lacking the RelA (p65) subunit of NF-κB die between days 14 and 15 of embryogenesis because of massive liver destruction.Missing: lethal | Show results with:lethal
  59. [59]
    Lymph node formation and B cell homeostasis require IKK-α ... - PNAS
    Nov 22, 2021 · The noncanonical NF-κB pathway is activated by a subset of stimuli including lymphotoxin-β receptor (LTβR) ligation by LTα1β2 or LIGHT (TNFSF14) ...
  60. [60]
    The roles and regulatory mechanisms of TGF-β and BMP signaling ...
    Jan 24, 2024 · Moreover, BMP signaling is critical in early limb bud development (Fig. ... BMPRII couples with RANK to activate p-Smad1/5/8 and NF-κB signaling ...
  61. [61]
    Glutamate activates NF-kappaB through calpain in neurons - PubMed
    NF-kappaB activation by calpain may mediate the long-term effects of glutamate on neuron survival or memory formation.
  62. [62]
    A caspase-3-like protease is involved in NF-kappaB activation ...
    Glutamate receptor stimulation reportedly activates NF-kappaB in vitro and in vivo, although underlying mechanisms remain to be elucidated.
  63. [63]
    Single-particle tracking uncovers dynamics of glutamate-induced ...
    This study demonstrates for the first time that glutamate stimulation leads to an increased mobility of single NF-κB p65 molecules in neurites of living ...
  64. [64]
    Epidermal growth factor receptor agonists increase expression of ...
    Epidermal growth factor receptor agonists increase expression of glutamate transporter GLT-1 in astrocytes through pathways dependent on phosphatidylinositol 3 ...
  65. [65]
    The Role of bFGF in the Excessive Activation of Astrocytes ... - PubMed
    In this study, we demonstrated that exogenous bFGF attenuated astrocyte activation by reducing the expression of glial fibrillary acidic protein (GFAP) and ...
  66. [66]
    Mitochondrial Manganese Superoxide Dismutase Prevents Neural ...
    Activation of NF-κB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of Mn-SOD and suppression of ...
  67. [67]
    NF-κB in Innate Neuroprotection and Age-Related ... - Frontiers
    Anti-apoptotic effects of NF-κB can be mediated by c-Rel containing dimers, which enhance neuronal resilience to oxidative stress by inducing Bcl-xL, MnSOD, ...
  68. [68]
    NF-KappaB in Long-Term Memory and Structural Plasticity in the ...
    Nov 24, 2015 · NF-κB is crucial for converting short-term to long-term memory, regulating neuroprotection, neuronal transmission, and structural plasticity in ...
  69. [69]
    Nuclear factor-kappaB regulates multiple steps of gliogenesis in the ...
    NF-κB activation continues in neocortical gliogenic progenitors following commitment and is important to inhibit the differentiation of oligodendrocyte ...
  70. [70]
    Novel insights into the role of NF-κB p50 in astrocyte-mediated fate ...
    A crucial role in the regulation of neuronal fate specification in adult hippocampal NPC is played by the NF-κB p50 subunit. NF-κB p50KO mice display a ...
  71. [71]
    Constitutive Nuclear Factor-κB Activity Is Required for Central ...
    Oct 1, 2002 · Together, these studies demonstrate that active NF-κB activity is present throughout the developing and adult nervous system and indicate that ...
  72. [72]
    NF-κB signalling regulates the growth of neural processes in the ...
    Apr 1, 2005 · Taken together, these findings suggest that different thresholds of NF-κB activity enhance neurite growth and neuronal survival. What drives ...Introduction · Materials and methods · Results · Discussion
  73. [73]
    Activation of Spinal NF‐κB/p65 Contributes to Peripheral ...
    Dec 24, 2013 · A number of recent studies have indicated that spinal NF-κB/p65 is involved in central sensitization, as well as pain-related behavior. Thus ...
  74. [74]
    Spinal NF-kB upregulation contributes to hyperalgesia in a rat model ...
    Jan 23, 2020 · These findings suggest that NF-κB/p65 plays a role in central sensitization. However, whether spinal NF-κB/p65 can also facilitate advanced knee ...
  75. [75]
    Nuclear Factor κB Signaling Regulates Neuronal Morphology and ...
    The results of the present study show that cocaine upregulates NFκB signaling in the NAc and that this signaling pathway is crucial for controlling the ...
  76. [76]
    Role of NFkB in Drug Addiction: Beyond Inflammation
    Jan 7, 2017 · With specific connection to drugs of abuse, it has been demonstrated that NFkB function positively regulates spine formation in the nucleus ...Abstract · NFkB: HISTORY AND... · DIVERSE ROLES AND GENE...
  77. [77]
    Induction of nuclear factor‐κB in nucleus accumbens by chronic ...
    Jul 7, 2008 · The main finding of this study is the identification of NF-κB subunits as targets of the transcription factor ΔFosB and of chronic cocaine ...<|control11|><|separator|>
  78. [78]
    Astrocyte-Derived Exosomal miR-148a-3p Suppresses ... - eNeuro
    Jan 25, 2024 · In addition, we evaluated ERK and NF-κB p65 expression to examine the effect of miR-148a-3p on the NF-κB signaling pathway after TBI. Brain ...Tbi Animal Model And... · Primary Microglia And... · Astrocytes Release Exosomes...
  79. [79]
    Neuroprotective effects of takinib on an experimental traumatic brain ...
    Apr 30, 2024 · Takinib had effectively inhibited the TAK1 activation and its downstream NF-κB inflammation signaling pathway. One limitation of the study stems ...
  80. [80]
    The presentation and natural history of immunodeficiency caused by ...
    Hypomorphic mutations in the NFκB essential modulator (NEMO) impair NFκB function and are linked to both immunodeficiency and ectodermal dysplasia (ED), as well ...
  81. [81]
    Immune deficiency caused by impaired expression of nuclear factor ...
    Mutations in the coding region of the IκB kinase γ/NF-κB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency.
  82. [82]
    Hypohidrotic ectodermal dysplasia and immunodeficiency ... - Frontiers
    Nov 8, 2011 · X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kB signaling. Nat. Genet. 27, 277–285. Pubmed ...
  83. [83]
    Defective nuclear IKKα function in patients with ectodermal ... - JCI
    Dec 12, 2011 · Our findings suggest that NEMO regulates the nuclear function of IKKα and offer new insights into the mechanisms underlying diminished NF-κB signaling in ...
  84. [84]
    Hematopoietic stem cell transplantation in 29 patients hemizygous ...
    Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT ...
  85. [85]
    Biochemically deleterious human NFKB1 variants underlie an ...
    Sep 2, 2021 · Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, ...
  86. [86]
    Human RELA dominant-negative mutations underlie type I ...
    Jun 5, 2023 · Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.
  87. [87]
    NF-kB signaling is the molecular culprit of inflamm-aging
    The NF-kB system is in the nodal point linking together the pathogenic assault signals and cellular danger signals and then organizing the cellular resistance.
  88. [88]
    NF-κB, a culprit of both inflamm-ageing and declining immunity?
    May 17, 2022 · NF-κB is generally recognized as an important regulator of ageing, through its roles in cellular senescence and inflammatory pathways.
  89. [89]
    Inflammageing: chronic inflammation in ageing, cardiovascular ...
    Of note, ROS produced by dysfunctional mitochondria can also trigger an inflammatory response by activating the NF-κB signalling pathway119.
  90. [90]
    Endothelial Nuclear Factor κB in Obesity and Aging | Circulation
    Feb 1, 2012 · Activation of NF-κB promotes local production of proinflammatory cytokines (IL-6, TNF-α), which downregulate insulin signaling via SOCS3 and JNK ...
  91. [91]
    Chronic Tumor Necrosis Factor-α Treatment Causes Insulin ...
    In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFα-induced insulin resistance in 3T3-L1 adipocytes. TNFα ...
  92. [92]
    Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3 ...
    Local and/or circulating TNF-α stimulates SOCS3 in adipocytes [21]. Both TNF-α and SOCS3 may increase insulin resistance via differing possible scenarios.
  93. [93]
    Chronic Adipose Tissue Inflammation Linking Obesity to Insulin ...
    Chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals.
  94. [94]
    Conditional and specific NF-κB blockade protects pancreatic beta ...
    In this report, we show that inhibition of the NF-κB pathway protects pancreatic beta cells from cytokine-induced apoptosis in vitro and in vivo from multiple ...Missing: review | Show results with:review
  95. [95]
    Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis ...
    We conclude that apoptosis is the main mode of FFA- and cytokine-induced β-cell death but the mechanisms involved are different. Whereas cytokines induce NF-κB ...
  96. [96]
    Major roles of kupffer cells and macrophages in NAFLD development
    May 19, 2023 · The activation of NF-kB pathway leads to an abundant amount of proinflammatory mediators as well as rallying of leukocytes.
  97. [97]
    Kupffer Cells in Non-alcoholic Fatty Liver Disease: Friend or Foe?
    Jun 23, 2020 · Activated NF-κB upregulates the levels of adhesion molecules and MCP-1, thus recruiting CD11b+ macrophages and promoting lipid synthesis, which ...
  98. [98]
    Modulation of NF-κB-dependent transcription and cell survival by the ...
    In conclusion, we found that SIRT1 represses NF-κB gene expression, in part, by deacetylating RelA/p65 at lysine 310. Future work will focus on identifying ...
  99. [99]
    SIRT1 Activators Suppress Inflammatory Responses through ...
    SIRT1, an NAD+-dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the ...
  100. [100]
    Caloric Restriction (CR) and CR Mimetics Alter Genome Function to ...
    Activated SIRT1 deacetylates the RelA/p65 component of NFκB, preventing degradation of IκB and sequestering NF-κB in the cytoplasm, inhibiting proinflammatory ...
  101. [101]
    Frontiers in sarcopenia: Advancements in diagnostics, molecular ...
    Additionally, NF-κB suppresses myogenic factors and impairs satellite cell function, hindering muscle regeneration and growth (Kim et al., 2023). Given its ...
  102. [102]
    Molecular constraints of sarcopenia in the ageing muscle - Frontiers
    Moreover, muscle aging is characterized by an upregulation of pathways related to immune response and inflammation, such as the “NF-κB signalling pathway,” “Jak ...
  103. [103]
    NF-κB: master regulator of cellular responses in health and disease
    Sep 4, 2025 · The transcription factor NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) was first identified in 1986 by Ranjan Sen and ...Missing: paper | Show results with:paper
  104. [104]
    Efficacy of Bortezomib as First-Line Treatment for Patients with ...
    Feb 28, 2013 · This review discusses several trials where Bortezomib has been used as a single/combination agent for front-line treatment of multiple myeloma.
  105. [105]
    Targeting IKKβ in Cancer: Challenges and Opportunities for the ...
    This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use ...
  106. [106]
    Clinical Use and Mechanisms of Infliximab Treatment on ... - NIH
    By blocking and neutralizing TNF activity, infliximab has shown its high effectiveness in the clinical management of Crohn's disease and ulcerative colitis. Up ...
  107. [107]
    Curcumin Blocks Cytokine-Mediated NF-κB Activation and ...
    We conclude that curcumin potently inhibits cytokine-mediated NF-κB activation by blocking a signal leading to IKK activity.
  108. [108]
    Inhibition of NF-κB Signaling Pathway by Resveratrol Improves ... - NIH
    Oct 4, 2018 · Resveratrol was found to enhance SIRT1 and AMPK expressions. Apoptotic expression is significantly suppressed by resveratrol on protein and mRNA ...
  109. [109]
    based PROTAC conjugates for the selective degradation of the NF ...
    May 8, 2025 · This project set out to develop PROTACs that can selectively degrade the NF-κB protein RelA/p65. The objective was to deplete this single NF-κB ...
  110. [110]
    NF-κB signaling and the tumor microenvironment in osteosarcoma
    Jan 29, 2025 · Broad inhibition of NF-κB could result in severe adverse effects, including immunosuppression and impaired wound healing. Consequently ...<|separator|>
  111. [111]
    NF-κB in Cancer Immunity: Friend or Foe? - PMC - PubMed Central
    (i) One possible mechanism relies on tumor cell-targeting effects of NF-κB inhibitors, which would in turn enhance immune responses. Tumor cell death ...
  112. [112]
    Development of RelB-targeting small-molecule inhibitors of non ...
    Apr 2, 2025 · Our study provided a new RelB-targeting inhibitor that inhibited the non-canonical NF-κB signaling pathway and facilitated precise therapeutic applications.
  113. [113]
    Modulation of NF-κB Signaling as a Therapeutic Target in ...
    This review focuses on the current strategies being investigated for the inhibition of the NF-κB pathway in autoimmune diseases and considers potential future ...
  114. [114]
    NfκBin: a machine learning based method for screening TNF-α ...
    In this study we have applied various machine learning algorithms to develop prediction models for screening of NF-κB inhibitors and non-inhibitors with higher ...
  115. [115]
    [PDF] In vivo CRISPR screening links NFKB1 to endocrine resistance in ...
    Aug 13, 2025 · Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro ...
  116. [116]
    NF-κB signaling is essential for resistance to heat stress-induced ...
    Sep 4, 2015 · Here, we present evidence that NF-κB signaling plays a crucial role in preventing heat stress-induced early apoptosis.Missing: climate- environmental
  117. [117]
    Dual Targeting of Inflammatory and Immune Checkpoint Pathways ...
    Jul 12, 2025 · Dual targeting of inflammatory and immune checkpoint pathways has shown potential to reverse radio resistance and enhance therapeutic response.