NF-κB: master regulator of cellular responses in health and disease.

Introduction

The transcription factor NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) was first identified in 1986 by Ranjan Sen and David Baltimore as a nuclear protein that binds to the enhancer element of the immunoglobulin κ light chain gene in B cells, thereby regulating antibody production [ 1 ]. This discovery proved to be pivotal in immunology, as it introduced NF-κB as a key transcriptional regulator whose functional scope extends beyond B cell biology, linking it to diverse cellular responses, including inflammation, immune regulation, stress adaptation, and cancer.

By the late 1980 s, researchers uncovered NF-κB’s role in viral pathogenesis, particularly in the replication of human immunodeficiency virus (HIV). It was observed that NF-κB binds to the long terminal repeat (LTR) of HIV, thereby facilitating viral transcription and contributing to latency and reactivation mechanisms [ 2 ]. This finding demonstrated the intricate interplay between host transcription factors and viral replication strategies, highlighting NF-κB as a potential target for antiviral interventions.

In the 1990 s, research efforts focused on elucidating the regulatory mechanisms governing NF-κB activation. A critical breakthrough was the identification of inhibitory proteins, termed IκBs, which sequester NF-κB in the cytoplasm under basal conditions [ 3 ]. The discovery of the IκB kinase (IKK) complex, which includes IKKα, IKKβ, and the regulatory subunit NEMO (IKKγ), provided mechanistic insight into NF-κB activation. Upon stimulation by pro-inflammatory signals such as tumor necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS), IKKβ phosphorylates IκBα, leading to its ubiquitination and proteasomal degradation. This degradation releases NF-κB, enabling its nuclear translocation and transcriptional activation of target genes [ 4 ]. The sufficiency of this mechanistic knowledge was demonstrated with mathematical models on the biochemical reaction network, which recapitulated observed activation kinetics in a variety of conditions [ 5 – 8 ].

Alongside the canonical pathway, a non-canonical NF-κB signaling cascade was identified, mediated by NF-κB-inducing kinase (NIK) and IKKα. Unlike the rapid canonical response, this pathway exhibits slower activation kinetics and is predominantly involved in lymphoid organ development, B-cell maturation, and adaptive immunity [ 9 , 10 ]. These two distinct but interconnected pathways underscore the versatility of NF-κB signaling in cellular physiology [ 11 ]. The mechanistic understanding of the interconnectedness of the two pathways was demonstrated by mathematical modeling of how the NF-κB signaling system mediates crosstalk in different cell types [ 12 ].

Structurally, NF-κB proteins belong to the Rel family, characterized by a conserved Rel homology domain (RHD) that mediates DNA binding, dimerization, and interaction with IκB inhibitors. The five NF-κB subunits in mammals-RelA (p65), RelB, c-Rel, p50/p105 (NF-κB1), and p52/p100 (NF-κB2) form various homo- and heterodimers, each exerting distinct transcriptional functions [ 13 ]. The composition of these dimers influences their regulatory roles [ 14 ], with RelA- and c-Rel-containing dimers predominantly driving gene activation, while RelB, p50 and p52 can function as transcriptional modulators depending on their interacting partners [ 15 ].

As a master regulator of immunity, NF-κB governs the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-6), chemokines (e.g., CXCL8), and adhesion molecules (e.g., ICAM-1), which are crucial for immune cell recruitment and signaling [ 16 ]. Additionally, it supports cell survival by upregulating anti-apoptotic genes such as BCL-2 and XIAP, ensuring immune cell persistence during inflammatory responses [ 17 ]. Beyond immunity, NF-κB is involved in embryonic development, particularly in lymphoid organogenesis and B cell differentiation, with RelB:p52 heterodimers playing a critical role in secondary lymphoid tissue formation [ 9 ].

Dysregulated NF-κB signaling contributes to various pathological conditions. In chronic inflammatory disorders such as rheumatoid arthritis (RA), persistent NF-κB activation drives synovial fibroblast proliferation and inflammatory cytokine release, exacerbating joint destruction [ 18 ]. Similarly, constitutive NF-κB activity is a hallmark of hematological malignancies, including Hodgkin’s lymphoma and diffuse large B cell lymphoma (DLBCL), where it promotes tumor cell survival, proliferation, and chemoresistance [ 19 ]. Furthermore, in neurodegenerative diseases such as AD, NF-κB activation in microglia exacerbates neuroinflammation by inducing pro-inflammatory cytokines and oxidative stress, accelerating neuronal damage [ 20 ].

Given its dual roles in normal physiology and disease, NF-κB represents a promising therapeutic target. However, broad NF-κB inhibition poses challenges due to its fundamental role in immune homeostasis. Targeting specific subunits (e.g., RelA) or upstream regulators (e.g., IKKβ) offers potential strategies for treating inflammation and cancer while minimizing systemic immunosuppression [ 21 ].

In this review, we will comprehensively examine NF-κB signaling, including its activation pathways, gene regulatory networks, physiological functions, and pathological implications. Additionally, we will discuss the latest advancements in therapeutic strategies targeting NF-κB in various diseases.

NF-κB activation pathways

Cells can activate NF-κB through two main signaling routes: the canonical pathway and the non-canonical pathway. The canonical NF-κB pathway is typically triggered by common external signals (such as infection or inflammation) and leads to a rapid activation of NF-κB and its target genes, driving immediate immune and inflammatory responses. In contrast, the non-canonical pathway is engaged by a more limited set of signals related to immune system development, and it acts more slowly to regulate genes involved in processes like lymphocyte development. While they share core components, the pathways differ in their triggers, timing, and roles, allowing NF-κB to coordinate both rapid defensive actions and longer term developmental processes. The next section will explore the canonical NF-κB pathway in detail, followed by the complementary non-canonical pathway (Fig. 1 ). Fig. 1 The Canonical and Non-Canonical NF-κB Pathways. The left diagram depicts the key molecular mechanisms of the canonical pathway that are engaged by TLRs, TNFR, and antigen receptors on B and T cells. They converge on the NEMO-containing IKK complex which phosphorylates canonical IκB proteins (e.g. IκBα) for degradation. Pre-existing NF-κB dimers (e.g. p50:RelA, also known as p50:p65) are released to translocate to the nucleus and bind target genes. The right diagram depicts the key molecular mechanisms initiated by BAFF-R, CD40 or LTβR. They converge on NIK and NEMO-less IKK, which phosphorylates the C-terminal domain of p100. C-terminal degradation of pre-existing p100 releases bound dimers (same as canonical pathway) and of newly-synthesized p100 allows for the generation of new p52 containing dimers (e.g. p52:RelB). BAFF-R, B-cell activating factor receptor; BCR, B-cell receptor; cIAP, cellular inhibitor of apoptosis protein; IKK, IκB kinase; IL1R, interleukin-1 receptor; IRAK, interleukin-1 receptor-associated kinase; LTβR, lymphotoxin-β receptor; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; NEMO, NF-κB essential modulator; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; NIK, NF-κB-inducing kinase; RIPK, receptor-interacting protein kinase; TAK1, transforming growth factor-β-activated kinase 1; TCR, T-cell receptor; TLR, Toll-like receptor; TNFR, tumor necrosis factor receptor; TRAF, TNFR-associated factor

Canonical NF-κB pathway

The canonical NF-κB pathway is a crucial signaling cascade activated by a diverse range of receptors, ultimately converging to induce the translocation of NF-κB to the nucleus. Prominent receptor systems involved include Toll-like receptors (TLRs), cytokine receptors such as TNFR1, and antigen receptors (TCR/BCR). Activation of TLR4 by bacterial LPS initiates a signaling cascade involving the recruitment of adaptor proteins MyD88 and TRIF [ 22 ]. The MyD88-dependent branch leads to the recruitment of IL-1 receptor-associated kinases (IRAK1/4), which, in turn, activate TNFR-associated factor 6 (TRAF6) through K63-linked ubiquitination. TRAF6 then facilitates the recruitment of the TGF-β-activated kinase 1 (TAK1) complex, leading to the phosphorylation and activation of the IKK complex (IKKα:IKKβ:NEMO) [ 23 ].

Upon binding of TNF-α, TNFR1 undergoes trimerization, leading to the recruitment of TNF receptor-associated death domain (TRADD) and the E3 ligases TRAF2 and RIPK1, forming the membrane-associated complex I. RIPK1 is then modified through K63-linked ubiquitination, creating a platform for the recruitment of TAK1 and the IKK complex. Subsequently, TAK1 phosphorylates IKKβ, which then phosphorylates IκBα, triggering its degradation [ 24 ].

Engagement of the T-cell receptor (TCR) or B-cell receptor (BCR) activates the protein kinase C (PKC) complex, including PKCθ, which phosphorylates the scaffolding protein CARD11. This event initiates the assembly of the CBM complex (CARD11-BCL10-MALT1), promoting K63-linked ubiquitination of NEMO/IKKγ. The CBM complex then recruits TAK1 and IKKβ, culminating in IKK activation and the liberation of NF-κB [ 25 ].

The IKK complex, a central regulator of the canonical NF-κB pathway, is composed of two catalytic subunits, IKKα and IKKβ, and the regulatory scaffold NEMO. Activation of the IKK complex is initiated by upstream kinases, most notably TAK1, which phosphorylates IKKβ at critical serine residues (Ser177/Ser181) within its activation loop. This phosphorylation event enhances IKKβ’s kinase activity, enabling it to phosphorylate IκBα at Ser32/Ser36. Phosphorylated IκBα is then recognized by the SCFβ-TrCP E3 ubiquitin ligase complex, which attaches K48-linked polyubiquitin chains to IκBα, targeting it for proteasomal degradation. This process releases NF-κB dimers (e.g., RelA:p50) for nuclear translocation and transcriptional activation of target genes [ 4 , 26 ]. There are several key steps in IKK activation, including: (1) NEMO’s regulatory role to stabilize the IKK complex and facilitate signal integration by interacting with ubiquitinated intermediates (e.g., RIP1, TRAF6); (2) TAK1 recruitment to form a complex with TAB1/2/3; (3) IKKβ Phosphorylation at Ser177/Ser181 to induce conformational changes, activating its catalytic activity; (4) IκBα targeting through IKKβ-dependent phosphorylation of IκBα at Ser32/Ser36, triggering its ubiquitination and degradation.

Following proteasomal degradation of IκBα, liberated NF-κB dimers (e.g., RelA:p50) are transported to the nucleus via the importin-α/β transport system. This process is facilitated by the exposure of the nuclear localization signal (NLS) on RelA, which is recognized by importin-α, while importin-β mediates passage through the nuclear pore complex [ 27 ]. In the nucleus, NF-κB dimers bind to conserved κB enhancer elements (5ʹ-GGGRNWYYCC-3ʹ) in the promoters of pro-inflammatory genes such as IL-6 and COX-2. The RelA subunit’s transactivation domains (TADs) play crucial roles in recruiting transcriptional co-activators [ 28 , 29 ]. Co-activators CBP/p300 are recruited to RelA, where their histone acetyltransferase (HAT) activity acetylates histones (e.g., H3K27), relaxing chromatin structure and enhancing the accessibility of the transcriptional machinery, enabling RNA polymerase II binding and initiation of transcription of numerous NF-κB-target genes [ 16 ].

The canonical NF-κB pathway is tightly regulated by negative feedback mechanisms to ensure transient inflammatory responses and prevent pathological hyperactivation. Key regulators include the classical or canonical IκBs, IκBα, IκBβ, IκBε, as well as IκBζ and BCL-3, which fine-tune NF-κB activity at multiple levels (Fig. 2 ). Newly synthesized IκBα, itself an NF-κB target gene, enters the nucleus and binds to NF-κB dimers (e.g., RelA:p50), displacing them from DNA [ 30 , 31 ]. This interaction masks the NLS of NF-κB, enabling export back to the cytoplasm via the CRM1/exportin-1 pathway. This rapid feedback loop [ 32 ] restores cytoplasmic sequestration of NF-κB [ 33 ], thereby either terminating the transcription of pro-inflammatory genes [ 5 , 34 ] or enabling reactivation if IKK activity persists [ 35 , 36 ]. Fig. 2 Negative Feedback and Cross-Regulation of the Canonical and Non-Canonical NF-κB Pathways. The diagram depicts negative feedback mechanisms via IκB proteins and A20 in the canonical pathway, and IKKα onto NIK in the non-canonical pathway. There are cross-talk mechanisms such as NIK activating the canonical NEMO-containing IKK complex or canonically-activated inducing p100 or A20 synthesis

Together, the negative feedback loops which also include IκBε [ 5 , 37 , 38 ], the IκBδ-containing IκBsome complex [ 39 , 40 ], and A20 [ 6 ] provide for complex dynamic control of NF-κB activity that is predictable and stimulus-specific [ 41 – 43 ]. In fact, despite single-cell heterogeneity, NF-κB dynamic control allows macrophage immune response genes to distinguish the stimulus ligand and dose with remarkable accuracy [ 8 , 44 ].

Negative regulators of NF-κB must also be synthesized in the steady-state to keep NF-κB activity low as there is non-zero constitutive IKK activity [ 45 – 47 ]. In fact, metabolic stress caused by UV irradiation or inducers of the unfolded protein response (UPR) activate NF-κB by causing a reduction of translational synthesis of IκB proteins via eIF-2α [ 48 – 50 ].

The classical IκBs bind NF-κB dimers but show distinct binding preferences, and responsiveness to canonical IKK activity. IκBα is the most responsive and shows preference for the ubiquitous RelA:p50 though it also shows affinity for c-Rel:p50 and RelB:p50 [ 51 ], while IκBε is less responsive and prefers c-Rel:p50 [ 38 , 52 – 54 ]. IκBβ has the highest affinity for RelA:RelA [ 55 ], is less responsive to IKK [ 5 ] and may function in the nucleus binding NF-κB dimers and protecting them from IκBα negative feedback [ 56 ].

IκBζ, another inducible IκB family member, modulates NF-κB activity by selectively interacting with specific p50-containing dimers. Unlike IκBα, IκBζ does not sequester NF-κB in the cytoplasm but instead alters its transcriptional output by competing for DNA binding or recruiting co-repressors. This mechanism fine-tunes subsets of NF-κB target genes, such as those involved in secondary immune responses [ 57 – 59 ]. BCL-3, a nuclear protein, associates with p50 or p52 homodimers to either enhance or repress transcription. By stabilizing these homodimers at κB sites, BCL-3 can suppress pro-inflammatory gene expression (e.g., IL-6) while promoting anti-inflammatory or survival genes. This duality allows BCL-3 to balance NF-κB outputs in a context-dependent manner [ 60 ]. These intricate feedback mechanisms ensure precise control over inflammation, preventing chronic activation linked to autoimmune diseases, cancer, and neurodegeneration. Dysregulation of IκBα, IκBζ, or BCL-3 is implicated in pathological states, highlighting their potential as therapeutic targets [ 61 ].

Dysregulation of the canonical NF-κB pathway is implicated in a variety of diseases, reflecting its critical role in inflammation, immunity, and cell survival. For instance, excessive activation of TLR4 by bacterial LPS leads to hyperactivation of the canonical NF-κB pathway, resulting in an uncontrolled release of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β). This “cytokine storm” induces systemic inflammation, endothelial dysfunction, and multi-organ failure. The MyD88-dependent arm of TLR4 signaling drives IRAK1/4-TRAF6-TAK1-mediated IKKβ activation, resulting in persistent nuclear translocation of RelA:p50 dimers and lethal immune hyperactivation [ 23 ]. Therapeutic strategies targeting NF-κB or upstream mediators (e.g., TLR4 antagonists) are being explored to reduce sepsis mortality.

Another example is constitutive IKKβ activity in intestinal epithelial cells, which promotes tumorigenesis by sustaining NF-κB-dependent transcription of pro-survival and metastatic genes. In colitis-associated colorectal cancer (CRC), chronic inflammation drives IKKβ phosphorylation of IκBα, enabling NF-κB to upregulate vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9). VEGF induces angiogenesis, while MMP9 degrades the extracellular matrix, facilitating tumor invasion and metastasis [ 62 ]. NF-κB also suppresses apoptosis by activating BCL-2 and XIAP, enhancing tumor cell survival. These examples illustrate the dual role of canonical NF-κB signaling in both host defense and pathology. In sepsis, strategies aimed at reducing excessive NF-κB activation (e.g., glucocorticoids, TAK1 inhibitors) are being investigated, while in CRC, IKKβ-selective inhibitors or anti-VEGF therapies (e.g., bevacizumab) are being developed to disrupt NF-κB-driven malignancy [ 63 ].

Non-canonical NF-κB pathway

The non-canonical NF-κB pathway is selectively activated by members of the tumor necrosis factor receptor superfamily (TNFRSF), which play a critical role in immune cell development, lymphoid organogenesis, and adaptive immunity. In contrast to the canonical pathway which releases pre-formed dimers and thereby responds rapidly upon stimulation, non-canonical signaling occurs over a longer timeframe (hours to days) as it depends on de novo protein synthesis and dimer formation.

Key receptors that activate the non-canonical pathway include BAFF-R, CD40, LTβR, RANK, and OX40, with BAFF-R and CD40 being particularly important in B cells for supporting survival, differentiation, and germinal center maintenance [ 10 , 64 ]. However, the non-canonical NF-κB pathway is also functionally important in T cells and other immune lineages. In T cells, TNFR superfamily receptors such as CD27, CD30, and 4-1BB (CD137) are key activators [ 65 , 66 ]. In dendritic cells, it modulates cytokine production and antigen presentation [ 67 , 68 ]. In osteoclasts, RANK-mediated non-canonical signaling is essential for differentiation and bone remodeling [ 69 ]. A distinct role is also emerging in epithelial and stromal cells where non-canonical activation integrates tissue-specific signals with immune cell function. Understanding the broader immunological relevance of this pathway, including its cell-type specificity and interplay with canonical NF-κB signaling, is essential for fully appreciating its contribution to immune regulation and for targeting it in disease contexts.

The key signaling event is the stabilization of NIK. Under normal conditions, NIK is continuously degraded via TRAF3-cIAP1/2-mediated ubiquitination. Activation of BAFF-R triggers TRAF3 degradation, leading to NIK accumulation. NIK then phosphorylates and activates IKKα, which leads to its degradation or proteolytic processing of either pre-existing p100 that is part of the oligomeric IκBsome complex [ 39 , 70 ] to release associated NF-κB dimers (e.g. RelA:p50, c-Rel:p50), or of newly synthesized P100 (NF-κB2) which allows for generation of new RelB:p52 or RelA:p52 dimers [ 64 , 71 ].

Expressed on antigen-presenting cells (APCs), CD40 interacts with CD40 ligand (CD40L) produced by activated T cells, initiating germinal center formation and antibody class switching. CD40 signaling leads to the recruitment of TRAF2/3 and cIAP1/2, resulting in TRAF3 degradation and NIK stabilization [ 72 ]. NIK-dependent NF-κB activation prolongs the proliferative potential of B cells and upregulates genes like activation-induced cytidine deaminase (AID) for somatic hypermutation [ 73 – 75 ]. In contrast, OX40 is expressed on T-cells and activates NIK, thereby regulating the developmental decision between effector and regulatory T cells (Tregs) [ 66 ].

Activation of LTβR by membrane-bound lymphotoxin (LTα1β2) on lymphocytes is essential for the development of secondary lymphoid organs (e.g., lymph nodes, Peyer’s patches). LTβR signaling recruits TRAF3 and NIK, leading to TRAF3 degradation and NIK accumulation. NIK activates IKKα, which phosphorylates p100, inducing its partial proteasomal processing to p52. The RelB:p52 dimer promotes stromal cell chemokine production (e.g., CXCL13) to organize lymphoid architecture [ 9 , 76 ], but also reduces the potential of RelA:p50 to activate inflammatory genes [ 77 ].

Key features of non-canonical signaling include: (1) kinetic delay as activation requires NIK stabilization and processing of newly synthesized p100, necessitating new protein synthesis; (2) selective outputs , which primarily regulates genes involved in lymphoid organogenesis, B cell survival, and adaptive immunity; and (3) crosstalk with canonical pathway as shared components like IKKα allow integration of signals in contexts like chronic inflammation [ 67 , 72 , 78 , 79 ].

The non-canonical NF-κB pathway is specifically regulated by the stabilization of NIK and subsequent activation of IKKα, which enables the controlled processing of the NF-κB2 precursor protein, p100. Under unstimulated conditions, NIK is maintained at low levels due to continuous proteasomal degradation. Zarnegar et al. [ 72 ] identified a critical regulatory complex comprising cIAP1, cIAP2, TRAF2, TRAF3, and NIK, which governs NIK stability and non-canonical NF-κB activation. In this complex, TRAF2 plays an essential role by recruiting and potentially activating cIAP1/2, which mediate the ubiquitination of NIK. TRAF3 functions as an adaptor, targeting the TRAF2/cIAP1/2 complex to NIK to facilitate its K48-linked ubiquitination and proteasomal degradation. cIAP1/2 conjugate K48-linked polyubiquitin chains to NIK, marking it for proteasomal degradation [ 80 ]. This coordinated assembly ensures tight regulation of NIK level and pathway activity.

Engagement of receptors such as BAFF-R, CD40, or LTβR triggers the disassembly of the TRAF3-cIAP1/2 complex. Receptor ligation induces TRAF3 degradation via K48-linked ubiquitination, mediated by cIAP1/2 auto-ubiquitination or recruitment of alternative E3 ligases [ 72 ]. The loss of TRAF3 prevents NIK ubiquitination, allowing NIK to accumulate and phosphorylate IKKα at Ser176/Ser180 [ 81 ]. Activated NIK phosphorylates and activates IKKα, which, in turn, phosphorylates the C-terminal region of p100 at specific serine residues (e.g., Ser866/Ser870). Phosphorylated p100 is recognized by the SCFβ-TrCP E3 ligase, which conjugates K48-linked ubiquitin chains to p100. This triggers partial proteasomal degradation of the C-terminal inhibitory ankyrin repeats, generating mature p52. This process occurs in the presence of RelB [ 82 ], resulting in the RelB:p52 dimer that then translocates to the nucleus, driving the transcription of genes involved in B-cell survival (BCL-2), lymphoid organogenesis (CXCL13), and immune regulation [ 9 , 64 ].

The maturation of p100 into p52 is a key event in the non-canonical NF-κB pathway, allowing for the selective activation of genes critical for immune development and homeostasis. This process involves regulated phosphorylation, ubiquitination, and partial proteasomal degradation. Activated IKKα, phosphorylated by NIK, targets the C-terminal region of p100 at Ser866/Ser870. This phosphorylation primes p100 for recognition by the SCFβ-TrCP E3 ubiquitin ligase complex [ 83 ]. SCFβ-TrCP conjugates K48-linked polyubiquitin chains to phosphorylated p100, marking it for proteasomal processing. Unlike canonical IκB degradation, the proteasome selectively removes the C-terminal inhibitory ankyrin repeats of p100 while sparing the N-terminal RHD, yielding mature p52 [ 82 , 84 ]. The newly formed RelB:p52 dimer is then transported to the nucleus, where it binds to κB enhancer elements to activate genes governing lymphoid organogenesis (e.g., CXCL13, CCL19) and B-cell survival (e.g., BAFF, BCL-2). These genes coordinate stromal cell organization in lymph nodes, Peyer’s patches, and splenic architecture, while sustaining B-cell maturation and tolerance.

The non-canonical pathway is regulated by a delicate balance of opposing factors. For example, He et al. [ 85 ] demonstrated that p100 deficiency rescues the lethal phenotype of TRAF3 knockout mice. TRAF3 is essential for maintaining low basal levels of NIK by promoting its degradation. In TRAF3 null mice, unchecked NIK accumulation drives excessive p100 processing into p52, resulting in hyperactivation of the non-canonical pathway and severe systemic inflammation. Deleting p100 restores viability by halting pathological NF-κB activation, highlighting the critical balance between TRAF3, NIK, and p100 in immune regulation [ 85 ].

The key pathological functions of the non-canonic NF-κB include cancer and autoimmunity. In 20% of multiple myeloma cases, mutations in TRAF3 or TRAF2 disrupt NIK degradation, leading to constitutive NIK accumulation. This drives excessive p100 processing to p52, promoting survival, proliferation, and chemoresistance of malignant plasma cells [ 86 ]. In Burkitt’s lymphoma, non-canonical NF-κB signaling cooperates with MYC oncogenes to enhance tumor cell survival and proliferation. RelB:p52 dimers suppress apoptosis while amplifying MYC-driven transcriptional programs [ 87 ]. Elevated BAFF level in systemic lupus erythematosus (SLE) prolong the survival of autoreactive B cells via RelB:p52-mediated BCL-2 expression. This results in autoantibody production and tissue damage, exacerbating disease progression [ 88 ].

The non-canonical NF-κB pathway exhibits distinct regulatory mechanisms that differentiate it from the canonical pathway, that render it particularly relevant to the pathology and therapeutic opportunity in cancer [ 64 ]. Dysregulation (e.g., NIK overexpression in B-cell malignancies) may provide sustained survival signals [ 89 ]. In association with autoimmunity, chronic BAFF-R signaling in autoreactive B cells leverages pathway specificity to evade apoptosis [ 75 , 90 ]. As potential therapeutic targeting, inhibitors of NIK or BAFF are tailored to exploit the pathway’s restricted activity, minimizing off-target effects [ 67 ].

Crosstalk between canonical and non-canonical pathways

The canonical and non-canonical NF-κB pathways, while distinct in their primary roles and activation mechanisms, share key components that enable crosstalk and synergistic signaling. This integration allows cells to mount coordinated immune and developmental responses. Mathematical modeling has helped reveal some key molecular mechanisms and how they are deployed in different cell types [ 12 ]. First, although NIK is central to the non-canonical pathway, it also amplifies canonical NF-κB activation in specific contexts. During TCR engagement, NIK stabilizes IKKβ by preventing its degradation, enhancing phosphorylation of IκBα and promoting nuclear translocation of RelA:p50 dimers. This synergy ensures robust T-cell activation and cytokine production, bridging rapid inflammatory responses with sustained signaling for adaptive immunity [ 80 ]. Zarnegar et al. [ 78 ] demonstrated that NIK directly interacts with the canonical IKK complex (IKKα:IKKβ:NEMO) to enhance canonical NF-κB activation. NIK facilitates IKKβ phosphorylation and stabilizes the IKK complex, enabling efficient IκBα degradation and NF-κB nuclear translocation. This mechanism operates in contexts such as CD40 signaling in B cells and TNF-α stimulation in epithelial cells, revealing NIK as a dual-pathway regulator [ 78 ].

Second, IKKα has dual phosphorylation roles in both pathways. IKKα phosphorylates IκBα at Ser32/Ser36, contributing to its ubiquitination and degradation. It also phosphorylates p100 at Ser866/Ser870, enabling its processing into p52. This duality allows IKKα to mediate both acute inflammation (via canonical) and longer term developmental processes (via non-canonical), depending on cellular stimuli [ 83 , 84 ]. Additional shared components among both canonical and non-canonical NF-κB pathways include ubiquitination machinery and proteasome. Both pathways rely on SCFβ-TrCP E3 ligase for substrate recognition and degradation/processing (IκBα in canonical, p100 in non-canonical), highlighting its role in regulating NF-κB dynamics, and rendering it a potential bottleneck that limits the positive crosstalk between the pathways [ 91 ].

There are several synergistic signaling examples between these two NF-κB pathways. During B-cell activation, BAFF-R (non-canonical) and TLR (canonical) co-stimulation drives simultaneous RelB:p52 and RelA:p50 or c-Rel:p50 activation, enhancing survival and inflammatory gene expression. During lymphoid organogenesis, LTβR signaling engages both pathways, with canonical NF-κB initiating stromal cell activation and non-canonical sustaining chemokine production [ 9 ]. In B cells, BCR and BAFF can optimize proliferation by engaging both pathways [ 75 ]. On the other hand, there are also pathological implications as the results of their synergistic signaling. In DLBCL, constitutive canonical signaling (via IKKβ) and NIK overexpression synergize to promote tumor survival and drug resistance [ 86 ]. In addition, dysregulated crosstalk in SLE amplifies autoreactive B-cell survival via BAFF-R (non-canonical) and TLR (canonical) synergy [ 88 ]. In the therapeutic perspectives, dual targeting of inhibitors of NIK or IKKα may disrupt pathological synergy in cancers and autoimmune diseases while sparing beneficial immune functions. In addition, context-specific drugs with compounds targeting shared components (e.g., proteasome inhibitors like bortezomib) exploit pathway overlap for conditions like multiple myeloma [ 81 ]. The discovery of NIK’s role in canonical signaling underscores its potential as a therapeutic target in diseases driven by hyperactive NF-κB. For example, NIK inhibitors could simultaneously dampen both pathways in malignancies like DLBCL, where crosstalk exacerbates tumor survival.

The interplay between the canonical and non-canonical NF-κB pathways amplifies disease progression in chronic inflammation and cancer [ 89 ]. Below are key examples of their synergistic roles in pathological contexts: In the case of chronic inflammation such as RA, TNF-α drives IKKβ-mediated activation of RelA:p50, inducing pro-inflammatory cytokines (e.g., IL-6, IL-8) and (MMPs that degrade joint tissue, while BAFF signaling via RelB:p52 upregulates anti-apoptotic genes (e.g., BCL-2), prolonging synovial fibroblast survival. TNF-α and BAFF synergize to sustain synovial hyperplasia and inflammation, perpetuating RA pathogenesis [ 18 , 88 ]. In the case of Hodgkin’s lymphoma, co-activation of canonical and non-canonical induces CCL5 expression, recruiting immunosuppressive regulatory T cells (Tregs) to the tumor microenvironment. Treg infiltration suppresses anti-tumor immunity, facilitating lymphoma progression and therapy resistance [ 92 ].

The NF-κB pathways are tightly regulated by negative feedback mechanisms to prevent excessive inflammation and maintain cellular homeostasis. Key feedback loops include p52 repression, the dual role of A20 (TNFAIP3), and IKKα-mediated NIK degradation, which modulate both canonical and non-canonical signaling as described below: (1) NF-κB inducible p50 homodimers lack TADs and compete with transcriptionally active dimers (e.g., RelA:p50) for binding to κB enhancer elements as well as subsets of interferon response elements [ 93 ]. By occupying κB sites in promoters of pro-inflammatory genes (e.g., IL-6, TNF-α), p52 homodimers suppress their expression, acting as transcriptional repressors. This limits inflammatory responses and restores equilibrium. The p50 repression balances immune activation by tempering canonical NF-κB outputs and is also critical in resolving inflammation and preventing tissue damage. (2) A20 deubiquitinates K63-linked ubiquitin chains on RIPK1, terminating TNF-α-induced NF-κB activation [ 6 ]. It was also reported to conjugate K48-linked ubiquitin to RIPK1, marking it for proteasomal degradation [ 94 ]. On the other hand, A20 also deubiquitinates TRAF3, stabilizing it to promote NIK degradation. This suppresses p100 processing into p52, dampening non-canonical signaling [ 81 ]. Therefore, A20 acts as a “brake” on both pathways, preventing hyperactivation linked to autoimmunity and cancer. A20 mutations are associated with lupus, RA, and B-cell lymphomas due to unchecked NF-κB activity [ 95 ]. (3) Razani et al. [ 79 ] identified a negative feedback loop in which IKKα phosphorylates NIK at specific residues (e.g., Ser809/Ser812), targeting it for proteasomal degradation. This occurs after non-canonical pathway activation, ensuring transient signaling and preventing NIK accumulation. By destabilizing NIK, IKKα limits the duration and intensity of non-canonical NF-κB signaling, maintaining immune homeostasis and prevents constitutive activation of the non-canonical pathway, which could otherwise lead to lymphoid hyperplasia or autoimmunity [ 79 ]. As potential therapeutic implications, enhancing p52 homodimer activity could mitigate chronic inflammation. Small-molecule A20 agonists may restore feedback control in autoimmune and inflammatory disorders [ 96 ]. Inhibiting IKKα’s kinase activity could extend NIK stability, potentially enhancing immune responses in immunodeficiency contexts. Conversely, promoting IKKα-mediated NIK degradation might suppress pathological NF-κB activation in cancers.

Transcriptional regulation by NF-κB dimers

The transcriptional regulation by NF-κB dimers is a highly dynamic and context-dependent process. The composition of NF-κB dimers, their binding specificity to κB enhancer elements, and their interactions with co-regulators and chromatin remodeling complexes all contribute to the precise control of gene expression. Additionally, post-translational modifications may provide a rapid and reversible mechanism for modulating NF-κB activity in response to cellular signals. The complexity of NF-κB signaling is further underscored by the fact that different NF-κB dimers can have distinct, and sometimes opposing, effects on gene expression. Understanding these regulatory mechanisms is crucial for elucidating the role of NF-κB in health and disease and for developing targeted therapeutic strategies [ 97 ].

Structure and composition of NF-κB dimers

The NF-κB transcription factors function as dimeric complexes composed of members of the Rel family: RelA (p65), RelB, c-Rel, p50 and p52. All five subunits share a conserved N-terminal RHD, which mediates DNA binding, dimerization, and nuclear localization. This ~ 300-amino-acid region encompasses key structural elements such as the DNA-binding loop, dimerization interface, and NLS [ 15 , 97 ]. In contrast, their C-terminal regions differ significantly and are crucial for functional specialization. Notably, RelA contains two TADs that confer transcriptional activity, c-Rel and RelB are thought to contain TADs though they have not been defined molecularly, while p50 and p52 lack TADs and often act as transcriptional repressors unless partnered with a TAD-containing co-activator [ 98 ].

The complete NF-κB repertoire includes 15 possible dimeric combinations, which span a broad functional landscape. As shown in Fig. 3 , these NF-κB complexes can be classified into four different subgroups: (1) The canonical inflammatory dimers consisting of RelA:p50, c-Rel:p50, RelB:p50, RelA:RelA, and c-Rel:c-Rel; (2) The non-canonical developmental dimers consisting of RelB:p52, RelA:p52, c-Rel:p52; (3) The non-DNA binding dimers consisting of RelB:RelA, RelB:c-Rel, and RelB:RelB; (4) The repressive dimers consisting of p50:p50, p52:p52, p50:p52 [ 14 , 15 , 41 ]. Fig. 3 Composition of NF-κB Dimers. There are 15 possible NF-κB dimers. 12 are capable of binding DNA, but 3 are repressive of gene expression by competing with activators, or by recruiting co-repressors. Of the 9 activating dimers, 3 are only induced by the non-canonical pathway, but 6 are activated by both pathways, though they are characterized more prominently in response to the canonical pathway. p65- and c-Rel-containing dimers are prominently activating which renders RelB as a de facto repressor when it competes for binding the same κB site

The structural basis for dimer formation and function has been elucidated through crystallographic studies [ 99 ]. Several key principles govern dimer assembly: (1) The RHD contains specific residues that determine which subunits can pair. For instance, RelA shows strong affinity for both p50 and p52, while RelB preferentially binds p52. (2) Each dimer makes unique contacts with DNA that broadly classify into a 9, 10, 11 base pair κB site elements. (3) Dimers containing TAD-bearing subunits (RelA, c-Rel) can directly recruit transcriptional machinery, while TAD-lacking dimers (p50:p50) often function as repressors. Recent cryo-EM studies have revealed additional complexity, showing that some dimers can adopt multiple conformational states depending on post-translational modifications or co-factor binding.

Binding specificity to κB enhancer elements

NF-κB dimers exert their transcriptional regulatory functions by binding to specific DNA sequences known as κB enhancer elements. These elements are typically 9 to 11 base pairs long and are found in the promoter or enhancer regions of target genes. The consensus sequence for κB sites is 5′-GGR ~ (3-5) ~ YCC-3′, where R is a purine, and Y is a pyrimidine. The spacing of the two half-sites determines which homo- or heterodimer class has the highest affinity [ 15 , 98 , 99 ]. The 9, 10, 11 rule of NF-κB dimer specificity indicates that a 9-base-pair site has the highest affinity for RelA:RelA and c-Rel:c-Rel homodimers; the 10-base-pair site has the highest affinity for RelA:p50, c-Rel:p50, RelB:p50, RelA:p52, c-Rel:p52, and RelB:p52 heterodimers; and the 11-base-pair site has the highest affinity for p50:p50 and p52:p52 homodimers. However, the exact sequence of κB sites can vary significantly, and this variability plays a crucial role in determining the binding affinity and specificity of different NF-κB dimers [ 99 – 102 ].

The binding affinity of NF-κB dimers to κB sites is influenced by several factors, including the sequence of the κB element, the composition of the NF-κB dimer, and the presence of additional regulatory proteins [ 97 ]. For example, RelA:p50 dimers tend to bind with high affinity to κB sites with a GGG core including GGGAMTNYCC, while RelB:p52 dimers may prefer slightly different sequences such as GGGAMTNYC and c-Rel-containing dimers prefer GGGGCTYYCC [ 3 ]. The sequence context surrounding the κB site can also influence NF-κB binding, as certain flanking sequences may enhance or inhibit dimer binding [ 98 ]. Some dimers bind as single units, while others (particularly homodimers) can form higher-order complexes on DNA containing multiple κB sites. Additionally, the presence of other transcription factors or co-regulators in the vicinity of the κB site can modulate NF-κB binding and activity [ 103 ].

The binding of NF-κB dimers to κB sites is not a static process but is dynamically regulated by various cellular signals. For example, the phosphorylation of NF-κB subunits can enhance their DNA-binding affinity, while the acetylation of histones surrounding the κB site can increase the accessibility of the DNA to NF-κB dimers [ 99 , 104 ]. NF-κB is effective in evicting or moving the histone octamer when its activity is sustained and non-oscillatory [ 105 , 106 ]. Conversely, the methylation of DNA or histones can downregulate NF-κB and its transcriptional activity [ 107 ]. These dynamic regulatory mechanisms allow cells to fine-tune NF-κB-mediated gene expression in response to changing environmental conditions. Genome-wide ChIP-seq studies have shown that RelA:p50 predominantly occupies promoters of immediate-early inflammatory genes, while RelB:p52 targets genes involved in lymphoid organogenesis and cell survival [ 108 ].

Transcriptional regulation by NF-κB

The transcriptional regulation of NF-κB is a highly dynamic and multi-layered process, integrating signal-responsive dimer formation, chromatin architecture, enhancer cooperation, and both positive and negative regulatory mechanisms. NF-κB dimers bind DNA at κB enhancer elements and coordinate the expression of a wide range of genes involved in immunity, inflammation, development, and cell survival [ 108 ].

NF-κB activates transcription through three principal mechanisms: chromatin remodeling, enhancer formation, and recruitment of components of the transcriptional machinery (Fig. 4 ). RelA contains two activation domains TA1 and TA2, making it one of the most potent mammalian transcriptional activators. When promoters or enhancer regions are accessible, NF-κB binds and recruits HATs, most notably CBP/p300 through molecular interactions that have been characterized in molecular structural detail [ 28 ]. This interaction is often but not always required for transcriptional activation of inflammatory response genes [ 29 , 109 ] indicating that other interactions with components of the transcriptional machinery may mediate the transcriptional activation of poised genes. Fig. 4 Model of NF-κB Transcriptional Regulation. There are numerous mechanisms by which NF-κB controls transcription. Some are alluded to here. Their interplay is gene- and context-specific, precluding general principles of transcriptional regulatory mechanisms

In addition, on inaccessible chromatinized promoters and enhancers, NF-κB has the ability to remodel chromatin. The first step is the movement or eviction of nucleosomes; this requires NF-κB activity of at least 2 or more hours [ 34 ] such that oscillatory NF-κB activity induced by TNF is unable to generate open chromatin [ 105 , 106 ]. Yet this step is thought to be mediated solely by competition with nucleosomal histones for DNA access and does not involve the RelA activation domains. In contrast, the next step, formation of enhancers with the transient histone modifications of H3K27Ac, and H3K4me3, which then turns into long-lasting H3K4me1 is thought to require the activation domains as well as the interaction with CBP/p300. Acetylation on histones and potentially other proteins facilitates access to the transcriptional start site and enables the binding of additional co-activators and transcription factors [ 103 ]. Chromatin remodeling complexes such as SWI/SNF are also engaged. These ATP-dependent complexes reposition nucleosomes, exposing DNA regions that were previously occluded.

NF-κB functions synergistically with other transcription factors including AP-1, IRFs, and STATs to form interactions that are not always well defined [ 110 – 113 ]. Through looping mechanisms, distal enhancers can be brought into close proximity with gene promoters, facilitating robust transcription initiation [ 98 ]. Additionally, elongation and processing factors promote productive transcription and ensure proper mRNA synthesis and NF-κB may play a role in this process [ 114 , 115 ]. While the RelA:p50 dimer is a potent activator of transcription via this cascade, RelB:p52 dimer, lacking a classical TAD, has roles in repression via competition as well as activation, potentially via alternative co-activators like BCL-3.

NF-κB family members also engage in repression to fine-tune transcriptional responses. Negative regulation ensures termination of inflammatory responses and restoration of basal gene expression. Dimers such as p50:p50 and p52:p52 lack TADs and act as transcriptional repressors. They compete with activating dimers for κB site occupancy [ 3 ] , as well as G-rich IRF response elements [ 116 ]. Their DNA binding occludes access to activators, thereby reducing gene expression responses to upstream signaling. They have also been reported to recruit histone deacetylases (HDACs), which remove acetyl groups and promote chromatin condensation. In addition, NF-κB binding sites may also be regulated through dimer exchange to prolong or terminate transcription [ 76 , 93 ]. After prolonged inflammatory stimulation, newly synthesized p50 accumulates and replaces RelA:p50 dimers on DNA. This switch effectively terminates the transcriptional program and restores quiescence. This dimer exchange is one of the key anti-inflammatory feedback mechanisms.

The complex interplay between activation and repression enables NF-κB to exert precise control over gene expression in response to dynamic extracellular cues. The ability to transition between transcriptional activation and repression underlies NF-κB's capacity to fine-tune responses in immunity, development, and stress adaptation.

Post-translational modifications influencing NF-κB activity

Post-translational modifications (PTMs) play a critical role in regulating NF-κB activity. Phosphorylation, acetylation, ubiquitination, and SUMOylation are among the most common PTMs that influence NF-κB signaling. These modifications can affect various aspects of NF-κB function, including its stability, localization, DNA-binding affinity, and interactions with other proteins [ 104 ].

Phosphorylation is one of the most well-studied PTMs of NF-κB and thought to be important for its activation and function. For example, phosphorylation of RelA at specific serine residues (e.g., Ser536) is an excellent marker of NF-κB activity [ 97 ]. It is the result of IKK activity whose primary function is IκBα phosphorylation, so whether S536 phosphorylation is functionally required or merely a passenger modification that is an excellent marker remains unclear [ 29 ]. Additionally, phosphorylation of other NF-κB subunits, such as p50 and RelB, was reported to influence their activity and function [ 104 ].

Acetylation of NF-κB subunits, particularly RelA, was also reported to enhance or repress their activity, depending on the specific lysine residue modified. For example, acetylation of RelA at Lys310 enhances its transcriptional activity by promoting interactions with co-activators and increasing its DNA-binding affinity [ 104 ]. In contrast, acetylation and ubiquitination of RelA at Lys221 can lead to its nuclear export and transcriptional repression [ 107 ]. There are no recent studies that have provided further clarification on these roles.

SUMOylation is a less well-studied PTM of NF-κB but has been shown to play a role in its regulation. SUMOylation of RelA can lead to its nuclear export and transcriptional repression, while SUMOylation of IκBα can stabilize it and prevent its degradation [ 104 ]. SUMOylation of other NF-κB subunits, such as p50 and RelB, can also influence their activity and function [ 117 ]. These PTMs provide an additional layer of regulation, allowing cells to rapidly adjust NF-κB activity in response to changing environmental conditions. The interplay between different PTMs and their effects on NF-κB function is subtle, complex and context-dependent, highlighting that further research of these regulatory mechanisms needs to be in specific physiological and pathological settings.

Biological functions of NF-κB

NF-κB plays a central role in a wide range of biological processes as shown in Fig. 5 . Its ability to regulate gene expression in response to diverse stimuli makes it a critical player in immunity, inflammation, cell survival, development, and metabolism. This chapter explores the multifaceted biological functions of NF-κB, focusing on its roles in immune and inflammatory responses, cell survival and proliferation, developmental processes, and other physiological roles. Fig. 5 Schematic Representation of NF-κB’s Physiological Roles. The schematic diagram summarizes the physiological roles of the canonical and non-canonical NF-κB pathway

Immune and inflammatory responses

NF-κB is perhaps best known for its role in regulating immune and inflammatory responses [ 14 , 16 ]. It acts as a key mediator of both innate and adaptive immunity, orchestrating the expression of cytokines, chemokines, adhesion molecules, and other immune-related genes. NF-κB is rapidly activated in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and plays essential roles in innate immunity [ 23 ]. TLRs, which recognize PAMPs such as bacterial LPS and viral RNA, are major activators of the canonical NF-κB pathway. Upon activation, NF-κB induces the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and chemokines (e.g., CXCL8, CCL2), which recruit immune cells to the site of infection or injury. NF-κB also regulates the expression of antimicrobial peptides and proteins that directly combat pathogens.

NF-κB is essential for the development, activation, differentiation, effector function, and memory formation of T cells. During thymic development, NF-κB signaling-particularly via the non-canonical pathway involving RelB:p52-is critical for the maturation and survival of medullary thymic epithelial cells (mTECs), which are essential for T cell tolerance and central deletion of autoreactive clones [ 118 ]. In RelB- or NF-κB2-deficient mice, impaired mTEC development leads to defective thymic architecture and disrupted negative selection, resulting in autoimmunity [ 9 , 10 ].

In peripheral T cells, antigen recognition through the TCR and co-stimulatory signals (e.g., CD28) activate the canonical NF-κB pathway. This activation induces IL-2 expression, promoting clonal expansion and survival [ 16 ]. NF-κB also regulates the transcription of lineage-defining cytokines and transcription factors, thereby guiding CD4⁺ T cell differentiation into distinct helper subsets (e.g., Th1, Th2, Th17, Treg) [ 119 ]. In CD8⁺ T cells, NF-κB controls positive selection [ 120 ].

Moreover, NF-κB plays a pivotal role in the generation and maintenance of T-cell memory. Sustained NF-κB activity, particularly involving c-Rel and RelA, supports metabolic fitness, survival, and epigenetic reprogramming of memory precursor cells [ 121 ]. Genetic deletion of c-Rel or disruption of IKKβ activity results in defective memory formation, reduced recall responses, and impaired long-term immunity [ 122 ].

In B cells, NF-κB activation is induced by BCR engagement and CD40 signaling, supporting survival, proliferation, and antibody production [ 14 , 75 , 123 , 124 ]. The non-canonical pathway is particularly important in promoting germinal center formation and class switch recombination through NIK-mediated processing of p100 to p52.

In addition, NF-κB is a central regulator of inflammation, driving the expression of genes involved in the inflammatory cascade [ 14 , 16 ]. In acute inflammation, NF-κB activation is transient and helps to eliminate pathogens and repair tissue damage. However, chronic activation of NF-κB can lead to persistent inflammation, contributing to the pathogenesis of inflammatory diseases such as RA, inflammatory bowel disease (IBD), and asthma [ 61 ]. NF-κB also plays a role in the regulation of inflammatory resolution by inducing the expression of anti-inflammatory mediators (e.g., IL-10) and promoting the clearance of apoptotic cells [ 4 ].

Cell survival and proliferation

As a critical regulator of cell survival and proliferation, NF-κB protects cells from cell death and promotes cell cycle progression [ 17 , 125 ]. Upon activation by pro-inflammatory cytokines (e.g., TNF-α), genotoxic agents, or PAMPs, NF-κB induces the expression of anti-apoptotic genes such as Bcl-2, Bcl-xL, c-IAPs, and FLIP. This anti-apoptotic program is critical for maintaining tissue integrity during inflammation, immune responses, and tissue repair [ 17 , 126 ]. For example, in T cells, NF-κB activation by TCR signaling upregulates anti-apoptotic genes, ensuring the survival of activated T cells during an immune response [ 16 ]. In addition, NF-κB plays a protective role against necroptosis via TNFAIP3/A20 [ 127 – 129 ] and in cells exposed to stress conditions such as oxidative stress, hypoxia, and DNA damage. For example, in response to oxidative stress, NF-κB induces the expression of antioxidant genes (e.g., SOD2) and DNA repair enzymes, helping cells to survive and maintain genomic stability [ 17 ]. In response to ER stress, NF-κB activation helps to restore protein homeostasis and prevent cell death [ 41 ]. NF-κB also plays a role in the DNA damage response, promoting the expression of DNA repair enzymes and cell cycle checkpoints [ 130 ].

NF-κB also regulates genes involved in cell cycle progression, such as cyclin D1 and c-Myc [ 14 , 123 ]. These proteins promote the transition from the G1 to the S phase of the cell cycle, facilitating cell proliferation. In cancer cells, aberrant NF-κB activation can lead to uncontrolled proliferation and resistance to apoptosis, contributing to tumorigenesis [ 19 ].

Developmental roles

NF-κB is involved in various developmental processes, including embryogenesis, tissue morphogenesis, and organ development [ 14 , 16 ]. Its role in development is context-dependent and varies across different tissues and stages of development. There is no evidence that NF-κB is activated during early embryogenesis but it is essential for the development of the immune system, nervous system, and other tissues. In particular, NF-κB is required for the developing immune system, typically by controlling survival of progenitors [ 14 , 122 ]. Other mechanisms have been elucidated that are required for differentiation per se [ 131 ]. There are many other reports in other systems. For example, NF-κB regulates the expression of genes involved in neural crest cell migration and differentiation, which are critical for the development of the peripheral nervous system and craniofacial structures [ 97 ].

NF-κB, particularly the non-canonical pathway, plays a crucial role in the development of secondary lymphoid organs such as lymph nodes, Peyer's patches, and the spleen [ 67 ]. RelB:p52 dimers regulate the expression of genes involved in the formation of lymphoid tissue structures and the recruitment of immune cells [ 9 ]. Mice deficient in NF-κB signaling components exhibit severe defects in lymphoid organ development and immune function [ 122 ]. In addition, NF-κB is involved in the morphogenesis of various tissues, including the skin, liver, and mammary gland. For example, NF-κB regulates the expression of genes involved in keratinocyte differentiation and skin barrier formation [ 61 ].

Other physiological roles

In addition to its roles in immunity, inflammation, cell survival, and development, NF-κB is involved in various other physiological processes, including metabolic regulation, stress responses, and aging [ 63 ]. NF-κB regulates metabolic processes by controlling the expression of genes involved in glucose and lipid metabolism. In adipose tissue, NF-κB activation promotes insulin resistance and inflammation, contributing to the pathogenesis of metabolic syndrome and type 2 diabetes [ 132 ]. In the liver, NF-κB regulates the expression of genes involved in gluconeogenesis and lipid metabolism, influencing systemic energy homeostasis [ 133 ].

In recent years, studies have revealed that NF-κB plays an essential role in regulating immunometabolism-the metabolic reprogramming of immune cells in response to activation and differentiation. In macrophages, NF-κB drives a shift toward aerobic glycolysis during inflammatory activation (M1 polarization), supporting the biosynthetic and energetic demands of cytokine production and phagocytosis. Conversely, anti-inflammatory (M2) macrophages rely more on oxidative phosphorylation, and NF-κB helps coordinate this transition via transcriptional control of metabolic enzymes and regulators [ 134 ]. Similarly, in T cells, NF-κB supports the metabolic reprogramming needed for effector function and memory differentiation by regulating glucose transporter expression and glycolytic flux [ 135 ]. These findings underscore NF-κB’s role as a key integrator of inflammatory signals and cellular metabolism in the immune system.

NF-κB has also been implicated in the aging process, with chronic activation of NF-κB contributing to age-related inflammation (inflammaging) and tissue degeneration [ 136 ].

NF-κB in disease associations

NF-κB is a central regulator of immune and inflammatory responses, cell survival, and development. While its activity is essential for maintaining cellular and organismal homeostasis, dysregulation of NF-κB signaling is implicated in the pathogenesis of a wide range of diseases as shown in Fig. 6 . This chapter explores the role of NF-κB in various disease contexts, including inflammatory diseases, cancer, neurodegenerative diseases, metabolic and cardiovascular disorders, and autoimmune diseases. Fig. 6 Schematic Representation of Abnormal NF-κB Activity in Diseases. The schematic diagram provides a general overview of the broad disease areas that NF-κB dysregulation has been implicated in. This renders NF-κB an attractive drug target in principle, though in practice the functional pleiotropy poses challenges to specificity and efficacy

Inflammatory diseases

NF-κB is a key driver of inflammation, and its dysregulation is a hallmark of many chronic inflammatory diseases [ 61 ]. Persistent activation of NF-κB leads to the overexpression of pro-inflammatory cytokines, chemokines, and adhesion molecules, contributing to tissue damage and disease progression. In RA, NF-κB is activated in synovial fibroblasts and immune cells, leading to the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [ 18 ]. These cytokines promote synovial inflammation, cartilage destruction, and bone erosion. NF-κB also regulates the expression of MMPs, which degrade extracellular matrix components and contribute to joint damage. Therapeutic strategies targeting NF-κB, such as TNF-α inhibitors, have been successful in treating RA [ 137 ].

In IBD, including Crohn's disease and ulcerative colitis, NF-κB activation in intestinal epithelial cells and immune cells drives chronic inflammation [ 61 ]. NF-κB regulates the expression of cytokines (e.g., TNF-α, IL-6) and chemokines (e.g., CXCL8) that recruit immune cells to the gut, leading to tissue damage and impaired barrier function. NF-κB also promotes the survival of inflammatory T cells, exacerbating the disease [ 63 ]. Anti-TNF therapies and other NF-κB inhibitors are used to manage IBD [ 137 ].

In asthma, NF-κB activation in airway epithelial cells and immune cells contributes to airway inflammation [ 138 ]. NF-κB regulates the expression of cytokines (e.g., IL-4, IL-5, IL-13) and chemokines (e.g., CCL11) that promote eosinophil recruitment and activation. NF-κB also induces the expression of adhesion molecules (e.g., ICAM-1, VCAM-1) that facilitate immune cell infiltration into the airways [ 139 ]. Targeting NF-κB signaling is a potential therapeutic strategy for asthma.

Chronically elevated NF-κB as a result of chronic inflammation associated with aging also has broad impact on the continuous production of blood cells. The resulting overproduction of myeloid cells was found to be driven by chronically elevated NF-κB affecting both the differentiation decision of hematopoietic stem cells (HSCs) towards myeloid progenitors and the enhanced proliferative expansion of such myeloid progenitors [ 140 , 141 ].

Cancer

NF-κB plays a dual role in cancer, acting as both a tumor suppressor and a tumor promoter depending on the context [ 19 ]. However, in many cancers, aberrant NF-κB activation promotes tumorigenesis, tumor survival, metastasis, and immune evasion. NF-κB activation is a common feature of many cancers, including lymphoma, breast cancer, and colorectal cancer [ 63 ]. In lymphoma, mutations in NF-κB signaling components (e.g., IKK, TRAF, NIK) lead to constitutive NF-κB activation, promoting cell survival and proliferation [ 86 ]. In solid tumors, NF-κB activation is often induced by inflammatory cytokines, growth factors, and oncogenic mutations. NF-κB regulates the expression of anti-apoptotic genes (e.g., Bcl-2, Bcl-xL) and cell cycle regulators (e.g., cyclin D1), contributing to tumor growth [ 17 ].

NF-κB promotes tumor survival by inducing the expression of anti-apoptotic genes and resistance to chemotherapy and radiation [ 19 ]. NF-κB also regulates the expression of genes involved in angiogenesis (e.g., VEGF) and extracellular matrix remodeling (e.g., MMPs), facilitating tumor invasion and metastasis [ 62 ]. In addition, NF-κB activation in tumor-associated immune cells (e.g., macrophages, T cells) creates an immunosuppressive tumor microenvironment, promoting immune evasion [ 142 ]. Given its role in tumorigenesis, NF-κB is a potential therapeutic target in cancer. However, the pleiotropic effects of NF-κB and its role in normal immune function pose challenges for targeted therapy. Current strategies include the use of proteasome inhibitors (e.g., bortezomib) to block NF-κB activation and the development of selective IKK inhibitors. Yet, such pharmacological strategies have to be carefully designed and vetted.

Neurodegenerative diseases

NF-κB is involved in both neuroprotection and neuroinflammation, and its dysregulation is implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [ 20 ]. In AD, NF-κB activation in microglia and astrocytes contributes to neuroinflammation and neuronal damage. NF-κB regulates the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1β) and reactive oxygen species (ROS), which promote amyloid-beta plaque formation and tau hyperphosphorylation. However, NF-κB can also have neuroprotective effects by promoting the expression of anti-apoptotic genes and neurotrophic factors [ 20 ]. In PD, NF-κB activation in microglia and dopaminergic neurons contributes to neuroinflammation and neuronal loss [ 20 ]. NF-κB regulates the expression of cytokines (e.g., TNF-α, IL-1β) and ROS, which promote α-synuclein aggregation and mitochondrial dysfunction. In ALS, NF-κB activation in motor neurons and glial cells contributes to neuroinflammation and motor neuron degeneration. NF-κB regulates the expression of cytokines (e.g., TNF-α, IL-1β) and ROS, which promote excitotoxicity and mitochondrial dysfunction. NF-κB also induces the expression of genes involved in apoptosis and axonal degeneration.

Metabolic and cardiovascular disorders

NF-κB plays a role in the pathogenesis of metabolic and cardiovascular disorders, including obesity, type 2 diabetes, and atherosclerosis [ 132 ]. In obesity and type 2 diabetes, NF-κB activation in adipose tissue, liver, and skeletal muscle contributes to insulin resistance and chronic inflammation. NF-κB regulates the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and chemokines (e.g., CCL2), which promote macrophage infiltration and adipose tissue inflammation [ 63 ]. In atherosclerosis, NF-κB activation in endothelial cells, smooth muscle cells, and macrophages drives plaque formation and progression [ 132 ]. NF-κB regulates the expression of adhesion molecules (e.g., ICAM-1, VCAM-1), cytokines (e.g., TNF-α, IL-1β), and chemokines (e.g., CCL2), which promote immune cell recruitment and foam cell formation. NF-κB also induces the expression of genes involved in vascular remodeling and plaque rupture.

In addition to its pro-inflammatory role, NF-κB directly disrupts insulin signaling through IKKβ-mediated phosphorylation of insulin receptor substrate 1 (IRS1) , leading to its degradation and impaired downstream signaling [ 143 ]. This interference diminishes activation of the PI3K/AKT pathway, a key driver of glucose uptake and metabolism in insulin-responsive tissues. Furthermore, NF-κB–driven cytokines activate suppressors of cytokine signaling (SOCS) proteins, which also inhibit IRS1 and insulin receptor function. These mechanisms illustrate how NF-κB acts as both an inflammatory and metabolic regulator, integrating nutrient excess, stress, and immune cues to impair insulin sensitivity and contribute to the pathogenesis of type 2 diabetes and metabolic dysfunction.

Autoimmune disorders

NF-κB activation is a key feature of autoimmune disorders, where it promotes the production of autoantibodies and immune dysregulation [ 88 ]. In SLE, NF-κB activation in B cells and dendritic cells drives the production of autoantibodies and immune complex formation. NF-κB regulates the expression of cytokines (e.g., IFN-α, IL-6) and chemokines (e.g., CXCL10), which promote immune cell activation and tissue damage [ 144 ]. In multiple sclerosis (MS), NF-κB activation in T cells and microglia contributes to neuroinflammation and demyelination [ 132 ]. NF-κB regulates the expression of cytokines (e.g., TNF-α, IL-17) and chemokines (e.g., CCL2), which promote immune cell infiltration into the central nervous system. NF-κB also induces the expression of genes involved in oligodendrocyte apoptosis and axonal damage. Interestingly, loss of function of RelB results in severe auto-inflammatory and autoimmune disease in patients and mice [ 145 , 146 ], driven by a dendritic cell hyperresponsiveness of inflammatory cytokines to RelA:p50, which usually must compete for κB sites with RelB-containing dimers [ 147 ].

Therapeutic targeting of NF-κB signaling

The schematic illustrates numerous drug classes that have been developed as inhibitors of excess NF-κB activity. They target the canonical and non-canonical NF-κB pathway at any level from receptor proximal to nuclear locations.

The central role of NF-κB in inflammation, immunity, and cancer has inspired extensive efforts to therapeutically target its signaling pathway (Fig. 7 ). Numerous components of the NF-κB cascade-including upstream receptors (e.g., TNFR, TLRs), adaptor proteins (e.g., MyD88, TRADD), kinases (e.g., IKKβ, TAK1), transcriptional subunits (e.g., RelA), and feedback regulators (e.g., A20)-have been proposed as drug targets. Early attempts focused on global NF-κB inhibitors such as proteasome inhibitors (e.g., bortezomib) and antioxidants. However, these broad-spectrum agents often led to unacceptable toxicity due to the ubiquitous and essential roles of NF-κB in immune homeostasis and host defense. Fig. 7 Drug Targeting Approaches Converge on NF-κB Pathways

Among the most clinically advanced strategies is the use of proteasome inhibitors like bortezomib, which indirectly block NF-κB activation by preventing IκBα degradation. Bortezomib has been approved for multiple myeloma and mantle cell lymphoma, where NF-κB is constitutively active [ 148 ]. Despite its success in these contexts, resistance mechanisms and systemic toxicities have limited its broader application across other diseases.

Targeting upstream kinases has also been pursued. For instance, IKKβ inhibitors such as MLN120B and SAR113945 showed promising anti-inflammatory effects in preclinical models [ 149 ]. However, clinical trials revealed challenges: SAR113945 failed to meet efficacy endpoints in a phase II trial for knee osteoarthritis ( NCT00782366 ), and other candidates were halted due to hepatotoxicity or narrow therapeutic windows. Dual inhibitors of IKKβ and TBK1, like TPCA-1 [ 150 ], encountered toxicity issues in animal models, preventing human translation.

Efforts to inhibit the non-canonical pathway have focused on targeting NIK, especially in B cell malignancies with constitutive NIK activation. Preclinical NIK inhibitors such as AM-0216 and CW15337 have shown efficacy in reducing RelB:p52 activity and suppressing tumor growth [ 151 ], but clinical translation remains ongoing.

Other strategies involve disrupting specific NF-κB dimers or their DNA-binding capabilities. Decoy oligonucleotides and peptide inhibitors targeting RelA:p50 dimers have shown therapeutic potential in models of inflammation and cancer [ 152 ]. Yet, drug delivery and stability challenges persist. More nuanced approaches are exploring context-specific modulation, such as targeting tissue-specific enhancers and epigenetic readers, or using proteolysis-targeting chimeras (PROTACs) to selectively degrade NF-κB subunits [ 153 ].

Despite the pathway’s attractiveness as a therapeutic target, the failure to develop blockbuster NF-κB-targeted drugs underscores its biological complexity. Reasons include the pleiotropic and context-dependent nature of NF-κB signaling, redundancy among family members, compensatory feedback loops, and risks of immunosuppression. These challenges emphasize the need for precision therapeutics that can modulate NF-κB selectively in pathological contexts without disrupting its essential physiological roles [ 154 ].

Moving forward, combination strategies (e.g., NF-κB inhibitors with immune checkpoint blockade), biomarker-driven trial designs, and improved delivery technologies may help realize the clinical promise of targeting NF-κB. Continued mechanistic insights and translational studies are essential to overcome prior limitations and develop more effective interventions against NF-κB-driven diseases. The following section reviews current pharmacological inhibitors of the NF-κB pathways, highlighting their mechanisms of action, clinical applications, and limitations as shown in Table 1 . Table 1 Summary of NF-κB inhibitors Inhibitor Class Compound Molecular Target Mechanism of Action Therapeutic Indications Clinical Status Receptor/Ligand Inhibitors Infliximab TNF-α TNF-α binding blockade Rheumatoid arthritis, Crohn's disease FDA-approved Adalimumab TNF-α TNF-α binding blockade Rheumatoid arthritis, Crohn's disease FDA-approved Anakinra IL-1R IL-1R signaling blockade Rheumatoid arthritis FDA-approved Denosumab RANKL RANKL-RANK interaction inhibition Osteoporosis, bone metastasis FDA-approved Belimumab BAFF BAFF signaling inhibition Systemic lupus erythematosus FDA-approved Etanercept TNF-α TNF-α blockade Rheumatoid arthritis FDA-approved Kinase Inhibitors ML120B IKKβ IKKβ kinase activity inhibition Inflammation, cancer Preclinical SAR 113945.00 IKKβ IKKβ inhibition Inflammation Preclinical BMS-345541 IKKβ IKKβ inhibition Inflammation, cancer Preclinical IKK-16 IKKβ IKKβ inhibition Inflammation Preclinical Zanubrutinib BTK BTK inhibition B cell malignancies FDA-approved Proteasome Inhibitors Bortezomib Proteasome Proteasomal degradation inhibition Multiple myeloma FDA-approved Carfilzomib Proteasome Proteasome inhibition Multiple myeloma FDA-approved Ixazomib Proteasome Proteasome inhibition Multiple myeloma FDA-approved Miscellaneous Agents Dimethyl fumarate Nrf2 Antioxidant response activation Multiple sclerosis FDA-approved Hydroxychloroquine Lysosome Lysosome function inhibition Lupus, autoinflammatory diseases FDA-approved Pyrrolidinedithiocarbamate (PDTC) ROS/Redox signaling Antioxidant, NF-κB inhibition Inflammation Preclinical Nrf2-inducing drugs Nrf2 pathway Nrf2 activation Inflammation Preclinical

Current pharmacological inhibitors of the NF-κB pathways

The NF-κB signaling pathways, encompassing both canonical and non-canonical routes, are integral to immune responses, inflammation, and cell survival. Dysregulation of these pathways is implicated in various diseases, including autoimmune disorders, cancers, and chronic inflammatory conditions. Consequently, several FDA-approved drugs have been developed to target components of these pathways. Below is a comprehensive description of current pharmacological inhibitors, categorized by their primary targets within the NF-κB signaling cascade, along with their mechanisms of action, clinical applications, and limitations.

Biologics

TNF-α is a key activator of the canonical NF-κB pathway, and its neutralization has proven highly effective in treating inflammatory diseases. There are several monoclonal antibodies that bind and neutralize TNF-α, including Infliximab (Remicade), Adalimumab (Humira), Golimumab (Simponi) and Certolizumab pegol (Cimzia) [ 137 ]. In addition, Etanercept (Enbrel), a fusion protein combining the TNFR with the Fc portion of IgG1, acts as a decoy receptor to bind TNF-α and lymphotoxin-α [ 155 ]. These anti-TNF-α therapies have revolutionized the treatment of autoimmune diseases such as RA, IBD, and psoriasis, significantly improving symptoms and quality of life. However, approximately 40% of patients develop antibodies against these biologics, reducing their efficacy over time [ 156 ]. In addition, TNF-α blockade increases the risk of infections, including tuberculosis and fungal infections [ 157 , 158 ].

BAFF is a critical activator of the non-canonical NF-κB pathway, promoting B-cell survival and maturation. Belimumab, a monoclonal antibody that neutralizes BAFF, dampening non-canonical NF-κB signaling, has been approved for SLE, where it reduces autoantibody production and disease activity. In clinical trials, belimumab reduced autoantibody titers by 60% in responders and improved overall disease management [ 148 ].

RANKL is a key activator of osteoclasts, and its inhibition suppresses NF-κB-mediated bone resorption. Denosumab (Prolia, Xgeva), a monoclonal antibody that binds to RANKL, preventing its interaction with RANK on osteoclasts has been approved for osteoporosis and bone metastases to reduce fracture risk and bone resorption [ 159 ]. The potential risks of RANKL inhibitor include hypocalcemia and osteonecrosis of the jaw [ 160 ].

IL-1 is a potent pro-inflammatory cytokine that activates NF-κB, making IL-1R antagonists valuable in treating inflammatory diseases. Anakinra (Kineret), a recombinant human IL-1R antagonist that blocks the activities of IL-1α and IL-1β, reducing NF-κB-mediated inflammatory responses is approved for RA and neonatal-onset multisystem inflammatory disease (NOMID) to reduce inflammation and disease activity in RA [ 161 ]. Its limitations include short half-life requiring daily injections and risk of infections. Canakinumab (Ilaris), a human monoclonal antibody targeting IL-1β, preventing its binding to IL-1R and subsequent NF-κB activation, is approved for cryopyrin-associated periodic syndromes (CAPS) and gouty arthritis [ 162 ]. The advantage of Canakinumab is its long-acting formulation with less frequent dosing while its limitations are high cost and risk of infections [ 163 ].

Kinase Inhibitors

ML120B is a selective inhibitor of IKKβ, the kinase responsible for phosphorylating IκBα in the canonical NF-κB pathway [ 164 ]. By blocking IKKβ activity, ML120B prevents IκBα degradation and subsequent NF-κB activation. In animal models of RA, ML120B significantly reduced synovial inflammation and joint destruction by suppressing pro-inflammatory cytokines like TNF-α and IL-6. Despite promising preclinical results, clinical trials revealed dose limiting hepatotoxicity, halting further development. SAR113945 is a dual inhibitor of IKKβ and IKKε, a kinase involved in both canonical and non-canonical NF-κB signaling [ 165 ]. It was developed to target inflammatory pathways in osteoarthritis. SAR113945 suppresses the expression of inflammatory mediators such as IL-1β and MMP13, which contribute to cartilage degradation. The drug exhibited poor oral bioavailability in clinical trials, limiting its therapeutic potential and leading to discontinuation of development.

BMS-986115 is a selective inhibitor of NIK, a key regulator of the non-canonical NF-κB pathway [ 166 ]. By targeting NIK, it blocks the processing of p100 to p52, thereby inhibiting NF-κB-driven gene transcription. In multiple myeloma animal models, BMS-986115 suppressed tumor growth and survival by disrupting NF-κB-dependent anti-apoptotic signals. It also showed efficacy in autoimmune models by reducing B-cell activation. Early-phase trials demonstrated limited efficacy in solid tumors due to compensatory activation of alternative survival pathways. Development was deprioritized in favor of combination therapies. INCB040093 is a potent, orally available NIK inhibitor designed to target both hematologic malignancies and autoimmune disorders [ 67 ]. It selectively blocks non-canonical NF-κB signaling, which is hyperactive in diseases like lupus and lymphoma. The drug inhibits NIK-dependent phosphorylation of IKKα, preventing RelB:p52 nuclear translocation and transcription of pro-survival genes. Clinical trials revealed immunosuppressive side effects, including increased susceptibility to infections, and development was discontinued due to an unfavorable risk-benefit profile.

Bruton’s tyrosine kinase (BTK) is a kinase involved in BCR signaling that leads to NF-κB activation, making BTK inhibitors effective in B-cell malignancies. Ibrutinib (Imbruvica), an irreversible inhibitor of BTK, blocking NF-κB signaling and B-cell proliferation has been approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenström’s macroglobulinemia to improve progression-free survival in CLL [ 167 ]. Side effects include bleeding, atrial fibrillation, and diarrhea. Acalabrutinib (Calquence), a second-generation BTK inhibitor with increased selectivity, reducing off-target effects while inhibiting NF-κB signaling, has been Approved for CLL and mantle cell lymphoma, showing improved safety profile compared to Ibrutinib [ 167 ]. However, it has risk of infections and bleeding. Zanubrutinib (Brukinsa), another second-generation BTK inhibitor targeting NF-κB pathway activation, has been approved for mantle cell lymphoma and Waldenström’s macroglobulinemia [ 168 ]. Zanubrutinib has high selectivity and reduced side effects but may have risk of infections and cytopenias.

Proteasome Inhibitors

Proteasome inhibitors prevent the degradation of IκBα, an inhibitor of NF-κB, thereby suppressing NF-κB activation. Bortezomib, a first-generation proteasome inhibitor, was the first drug in its class to be approved by the FDA [ 169 ]. It works by selectively inhibiting the 26S proteasome, a large protease complex responsible for degrading ubiquitinated proteins, including IκBα. By preventing IκBα degradation, bortezomib traps NF-κB dimers (e.g., RelA:p50) in the cytoplasm, blocking their transcriptional activity. Bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma, where constitutive NF-κB activation drives tumor survival and resistance to apoptosis. In multiple myeloma, Bortezomib has significantly improved response rates and overall survival, particularly in combination with other therapies like dexamethasone. As the potential limitations, approximately 30% of patients experience dose-limiting peripheral neuropathy, which can necessitate dose reduction or discontinuation [ 170 ]. Mutations in the PSMB5 subunit of the proteasome, the primary target of Bortezomib, can lead to resistance, limiting its long-term efficacy. Carfilzomib (Kyprolis), an irreversible proteasome inhibitor that also leads to the accumulation of IκBα, inhibiting NF-κB activity has been approved for relapsed or refractory multiple myeloma [ 171 ]. It has reduced neurotoxicity compared to Bortezomib but shows potential risk of cardiac toxicity and infusion-related reactions. Ixazomib is a second-generation, orally bioavailable proteasome inhibitor designed to address some of the limitations of Bortezomib [ 172 ]. Like Bortezomib, it inhibits the 26S proteasome, preventing IκBα degradation and NF-κB activation. Ixazomib is currently in Phase III trials for relapsed multiple myeloma and has shown promise in combination with lenalidomide and dexamethasone. Unlike Bortezomib, which requires intravenous or subcutaneous administration, Ixazomib can be taken orally, improving patient convenience. Ixazomib also has a lower incidence of peripheral neuropathy compared to Bortezomib, making it a safer option for long-term use.

Miscellaneous NF-κB Inhibitors

In addition to the abovementioned agents that directly bind to and inhibit a specific signaling molecules of the NF-κB pathways, there are multiple miscellaneous NF-κB inhibitors that inhibit NF-κB through indirect or off-target pathways. While effective in managing inflammation and immune dysregulation, their use is often limited by systemic toxicity, emphasizing the need for targeted NF-κB therapies.

Dexamethasone and prednisone indirectly suppress NF-κB signaling by enhancing IκBα synthesis to sequester NF-κB in the cytoplasm and/or recruiting co-repressors (e.g., GRIP1) via glucocorticoid receptors (GR), blocking NF-κB transcriptional activity [ 173 ]. These drugs are used in cytokine storms (e.g., COVID-19), RA, asthma, and allergic reactions. However, long-term use causes osteoporosis, immunosuppression (infection risk), and metabolic side effects (weight gain, diabetes, hypertension) [ 174 ].

Hydroxychloroquine inhibits TLRs (TLR7/9), reducing upstream NF-κB activation and pro-inflammatory cytokine production, which is used to treat autoimmune diseases like SLE and RA [ 175 ]. Its limitations include retinal toxicity with prolonged use, cardiac arrhythmias (QT prolongation), and limited efficacy in severe inflammatory conditions [ 176 ].

Aspirin is a non-selective COX inhibitor with secondary NF-κB inhibition via IKKβ suppression, preventing IκBα phosphorylation and degradation [ 177 ]. It is primarily used for pain, fever, and cardiovascular protection (antiplatelet effects). NF-κB inhibition contributes to anti-inflammatory benefits in chronic diseases. Potential concerns include gastrointestinal bleeding, renal toxicity, and Reye’s syndrome in children [ 178 ].

Thalidomide (Thalomid®), Lenalidomide (Revlimid®), and Pomalidomide (Pomalyst®) bind cereblon, promoting degradation of transcription factors (Ikaros, Aiolos), leading to downregulation of NF-κB activity and cytokine production (e.g., TNF-α, IL-6) [ 179 ]. They are used to treat multiple myeloma, myelodysplastic syndromes, and leprosy (thalidomide). Side effects include teratogenicity (strict contraindication in pregnancy), neuropathy (thalidomide), and immunosuppression (infection risk).

Challenges and limitations of current pharmacological inhibitors of the NF-κB pathways

While targeting the NF-κB pathways has shown promise in treating inflammatory diseases, autoimmune disorders, and cancers, several challenges and limitations hinder their widespread clinical application. These include pleiotropic effects, pathway redundancy, and paradoxical tumor-promoting effects, which complicate therapeutic strategies. Below is a detailed discussion of these challenges, supported by references.

Compromised Host Defense

NF-κB is a master regulator of innate and adaptive immunity, playing a critical role in defending against infections. Global inhibition of NF-κB can suppress immune responses, increasing susceptibility to infections. For example, TNF-α is essential for granuloma formation and containment of intracellular pathogens like Mycobacterium tuberculosis . Anti-TNF-α agents (e.g., infliximab, etanercept) have been associated with tuberculosis reactivation in patients with latent infections. This has led to mandatory screening for tuberculosis before initiating therapy [ 157 ]. Bortezomib, while effective in multiple myeloma, can impair immune cell function, increasing the risk of viral reactivation (e.g., herpes zoster) and bacterial infections [ 180 ]. Therefore, therapies targeting NF-κB must balance anti-inflammatory or anti-tumor effects with the preservation of host defense mechanisms.

Bypassing NF-κB Blockade

Cancer cells often exploit redundant signaling pathways to evade NF-κB inhibition, leading to treatment resistance. In Hodgkin’s lymphoma, NF-κB inhibition can be bypassed through activation of the STAT3 pathway, which promotes survival and proliferation of tumor cells. This redundancy limits the efficacy of NF-κB-targeted therapies [ 181 ]. In some cancers, inhibition of NF-κB leads to compensatory activation of the PI3K/AKT pathway, which supports cell survival and resistance to apoptosis [ 182 ]. Therefore, combination therapies targeting both NF-κB and parallel pathways (e.g., STAT3 or PI3K/AKT inhibitors) may be necessary to overcome resistance.

Paradoxical Tumor-Promoting Effects

In certain contexts, NF-κB inhibition can have unintended consequences, such as accelerating tumor progression or impairing immunosurveillance. NF-κB inhibition in pancreatic ductal adenocarcinoma (PDAC) has been shown to eliminate immunosurveillance by suppressing the production of chemokines that recruit anti-tumor immune cells (e.g., T cells, NK cells). This paradoxically accelerates tumor progression by creating an immunosuppressive microenvironment [ 183 ]. In some cases, NF-κB inhibition disrupts the balance between pro- and anti-inflammatory signals, promoting tumorigenesis through mechanisms such as increased oxidative stress and DNA damage [ 62 ]. The dual role of NF-κB in both promoting and suppressing tumorigenesis necessitates careful patient stratification and context-specific therapeutic approaches.

Toxicity and Side Effects

Many NF-κB inhibitors exhibit dose-limiting toxicities, which restrict their clinical utility. Bortezomib causes peripheral neuropathy in up to 30% of patients, often requiring dose reduction or discontinuation. Second-generation inhibitors like Ixazomib aim to reduce neurotoxicity but may still have off-target effects [ 184 ]. IKKβ inhibitors like ML120B/BMS-345542 have shown hepatotoxicity in clinical trials, limiting their therapeutic window [ 164 , 185 ]. Developing safer, more selective inhibitors with fewer off-target effects is a priority for future research. In addition, targeting the dynamic phases of NF-κB activity more precisely is another innovative strategy [ 186 – 188 ].

Limited Efficacy in Heterogeneous Diseases

The efficacy of NF-κB inhibitors varies widely across diseases and patient populations, reflecting the complexity and heterogeneity of NF-κB signaling. While anti-TNF-α therapies are highly effective in RA and IBD, up to 40% of patients do not respond due to genetic or epigenetic factors [ 137 ]. In addition, NF-κB inhibitors have shown limited efficacy in solid tumors, where compensatory pathways and tumor microenvironment interactions often dominate. To address these issues, personalized medicine approaches, including biomarker-driven patient selection, may improve outcomes by identifying individuals most likely to benefit from NF-κB-targeted therapies.

Emerging strategies for therapeutic targeting of NF-κB

The complexity and context-dependent roles of NF-κB signaling have spurred the development of innovative therapeutic strategies. These approaches aim to enhance specificity, overcome resistance, and minimize off-target effects. Below is a detailed exploration of emerging strategies, including subunit-specific targeting, PROTACs, gene editing, nanomedicine, and immunotherapy synergy, supported by references.

Subunit-Specific Targeting

Lipid-based nanoparticles deliver small interfering RNA (siRNA) targeting RELA to inflamed tissues, such as joints in RA. Preclinical studies show significant reduction in IL-6 and other pro-inflammatory cytokines without systemic toxicity. Localized delivery minimizes off-target effects and enhances therapeutic precision [ 189 ].

Compounds have been sought to selectively inhibit c-Rel DNA binding, blocking its transcriptional activity. They may demonstrate potent anti-tumor effects in T-cell lymphoma xenografts by suppressing c-Rel-dependent survival genes, which potentially offers a targeted approach for hematologic malignancies with minimal impact on other NF-κB subunits [ 122 ].

PROTACs (Proteolysis-Targeting Chimeras)

A NIK-directed PROTAC that recruits the ubiquitin–proteasome system to degrade NIK, a key regulator of the non-canonical NF-κB pathway. It overcomes bortezomib resistance in multiple myeloma by eliminating NIK-driven survival signals, which provides a novel strategy to target proteins traditionally considered “undruggable” [ 190 ].

Currently in phase I trials for hematologic malignancies, showing promise in disrupting oncogenic NF-κB signaling, dBET6 targets BRD4, a transcriptional co-activator of NF-κB, for proteasomal degradation. It combines epigenetic and NF-κB modulation for enhanced anti-tumor effects [ 191 ].

Gene Editing

REL knockout using the CRISPR/Cas9 technology in chimeric antigen receptor (CAR) T cells reduces NF-κB activity, mitigating cytokine release syndrome (CRS) while preserving anti-tumor efficacy. In B-cell acute lymphoblastic leukemia (B-ALL) patients, this approach reduces CRS by 70%. It enhances the safety profile of CAR-T therapy without compromising therapeutic outcomes [ 192 ].

Precision editing of RelA Ser536 to alanine using the base editing technology in macrophages blunts NF-κB activation and TNF-α production, which demonstrates significant anti-inflammatory effects in sepsis models. It also potentially offers a highly specific method to modulate NF-κB signaling in immune cells [ 193 ].

Nanomedicine

Conjugated with IKKβ inhibitors (e.g., PS-1145), the gold nanoparticles selectively accumulate in atherosclerotic plaques, which reduces VCAM-1 expression by 80% in ApoE ⁻/⁻ mice, attenuating inflammation and plaque progression. Targeted delivery enhances therapeutic efficacy while minimizing systemic side effects [ 132 ].

Tumor-derived exosomes loaded with IκBα super-repressor silence NF-κB in metastatic breast cancer cells suppress NF-κB-driven metastasis and enhance chemotherapy sensitivity. This exosome-based delivery utilizes natural system for precise and efficient therapeutic targeting [ 194 ].

Immunotherapy Synergy

The PD-1/NF-κB dual blockade by combining anti-PD-1 antibodies with IKKβ inhibitors enhances T-cell infiltration and anti-tumor immunity in NF-κB-high melanomas. It demonstrates superior tumor regression compared to monotherapy in preclinical models. It also addresses resistance to immune checkpoint inhibitors by targeting NF-κB-mediated immunosuppression [ 195 ].

Oncolytic viruses via engineered adenoviruses (e.g., ONCOS-102) lyse tumor cells while delivering IκBα to suppress NF-κB in the tumor microenvironment, which reduces tumor growth and enhances immune cell infiltration in solid tumors. The advantages of this approach are to combine direct oncolysis with immune modulation for a multi-pronged anti-tumor approach [ 196 ].

Future directions and open questions in the field of NF-κB

The NF-κB signaling network has been extensively studied for over three decades, yet it continues to reveal surprising complexity and new biological insights. While significant progress has been made in understanding its role in immune regulation, inflammation, and disease pathogenesis, several key questions remain unresolved. The future of NF-κB research lies in integrating molecular mechanisms with systems-level insights and exploiting these pathways for precision medicine. This section outlines major emerging directions and open challenges in the field.

Mechanistic insights and signaling specificity

NF-κB activation is mediated by a family of Rel proteins that form various homo- and heterodimers, yet to what extent and how different dimer combinations produce gene-specific outcomes remains poorly understood. Subtle sequence differences in κB sites [ 15 , 100 , 197 , 198 ] can alter which dimer binds and which coactivators are recruited, but whether this “NF-κB code” applies broadly in vivo is still unclear [ 98 ]. Elucidating how dimer composition, cofactor associations, and DNA sequence jointly encode target selectivity is a major open question.

The spatiotemporal dynamics of NF-κB signaling also encode critical information. Live-cell and single-cell studies have shown that different stimuli (e.g., TNF versus IL-1) elicit distinct patterns of NF-κB nuclear translocation such as sustained versus oscillatory or pulsatile activity and that these temporal patterns translate into specific transcriptional and epigenetic outcomes [ 105 , 199 – 210 ]. How these dynamic patterns are interpreted by gene regulatory networks and how feedback (e.g., autocrine loops, IκB synthesis) shapes them remain the active research areas.

PTMs add another layer of regulation. NF-κB subunits (especially RelA/p65) undergo extensive modifications-phosphorylation, acetylation, methylation, ubiquitination, etc. that fine-tune their activity and promoter selectivity [ 104 ]. How specific combinations of PTMs dictate function-and how NF-κB cooperates with chromatin remodelers (e.g., SWI/SNF, Akirin complexes) to access target genes are important open questions. Deciphering how cell-type-specific epigenetic states influence NF-κB binding and how NF-κB in turn reshapes chromatin (e.g., via enhancer activation) is an exciting frontier.

The non-canonical (alternative) NF-κB pathway adds further complexity. Activation of NIK and IKKα drives processing of p100 into p52 and activation of RelB:p52 and RelA:p52, typically in response to TNFRSF signals like BAFF or CD40. Yet, deficiency of NF-κB2 and RelB results in inflammatory disease in humans and mice, due to competition with RelA:p50 dimers [ 77 ]. How canonical and non-canonical signaling intersect in various contexts is still under study. For example, canonical NF-κB can induce transcription of NF-κB2, and canonical signals may prime cells to respond differently to non-canonical inputs. Recent genetic screens have begun to uncover unexpected regulators of non-canonical NF-κB: one genome-wide CRISPR/Cas9 screen [ 211 ] showed that loss of TRAF3 (a known NIK inhibitor) derepresses non-canonical NF-κB and drives aberrant proliferation. Future work will need to map how these two branches of NF-κB cross-regulate each other and integrate signals in chronic inflammation and immunity.

Therapeutic and clinical perspectives

NF-κB is central to many diseases (cancer, autoimmunity, chronic inflammation, neurodegeneration, aging-related disorders), making it an attractive therapeutic target. Indeed, drugs that blunt NF-κB effectors (e.g., anti-TNF-α antibodies, IL-1R antagonists, JAK inhibitors) have transformed treatment of autoimmune diseases like RA, IBD, and psoriasis (via reduction of NF-κB-driven cytokine expression). However, global NF-κB inhibition poses significant challenges. For instance, anti-TNF therapies, while highly effective in autoimmune inflammation, carry a high risk of reactivating latent infections. Patients on TNF-α blockers have markedly increased rates of tuberculosis and other intracellular infections [ 158 ]. More broadly, inhibiting NF-κB can impair host immune surveillance. In cancer, blocking NF-κB in tumor cells can sometimes be offset by loss of anti-tumor immunity, as illustrated in pancreatic cancer models where NF-κB blockade actually suppressed chemokine production and accelerated tumor growth by blunting immune cell recruitment [ 183 ]. These examples underline the need for context-specific targeting.

Moving forward, precision approaches will be essential. Subunit- or cell-type-specific modulation (e.g., siRNA or PROTACs targeting RelA in synovial cells, or targeting c-Rel in lymphoma cells) might achieve anti-inflammatory or anti-tumor effects while sparing normal immune functions [ 21 ]. Combination therapies are another avenue: NF-κB inhibitors may synergize with checkpoint blockade or with drugs targeting parallel pathways to overcome resistance. Importantly, NF-κB’s role in neurodegenerative and aging-related diseases is only beginning to be explored. Chronic NF-κB activation (“inflammaging”) is implicated in AD, PD, and other disorders, suggesting that anti-inflammatory or senolytic strategies (e.g., dasatinib + quercetin) that reduce NF-κB-driven senescence-associated secretory phenotype might improve healthspan [ 132 ]. Ultimately, translating NF-κB biology into therapy will require biomarkers to identify the patients and contexts most likely to benefit (e.g., tumors or patients with NF-κB “addiction” versus those reliant on compensatory pathways).

Systems biology and emerging technologies in NF-κB research

Recent advances in systems biology and integrative analysis have significantly deepened our understanding of the NF-κB signaling network. High-throughput transcriptomic, proteomic, and epigenomic datasets have enabled detailed mapping of NF-κB-regulated gene programs across diverse cell types and conditions. Integrative network modeling has been instrumental in uncovering feedback loops, signaling crosstalk, and context-specific NF-κB responses. For example, computational models have identified key regulators of NF-κB oscillations, timing, and stimulus-specific transcriptional outputs, providing mechanistic insights into how different stimuli yield distinct cellular responses through the same core pathway.

Single-cell RNA-seq and single-cell ATAC-seq have further revealed the cell-to-cell heterogeneity of NF-κB activity, showing that stimulus strength, chromatin accessibility, and transcriptional noise all contribute to differential pathway activation. Additionally, multi-omics approaches that integrate epigenetic, transcriptomic, and proteomic layers have elucidated how NF-κB cooperates with other transcription factors and signaling pathways in context-dependent gene regulation, such as in inflammation, development, and cancer.

In parallel, emerging experimental technologies have enabled high-resolution dissection of NF-κB signaling dynamics. Live-cell imaging using fluorescently tagged NF-κB subunits (e.g., p65-EGFP) has allowed real-time visualization of nuclear translocation, oscillatory behavior, and signal duration at the single-cell level. Optogenetic and chemically inducible systems provide precise temporal control of pathway activation, facilitating studies on stimulus response relationships and signaling thresholds.

Moreover, genome editing tools such as CRISPR/Cas9 and CRISPR interference (CRISPRi) have been used to dissect the functions of individual NF-κB subunits, upstream regulators, and target genes. These tools have advanced functional screening approaches to identify novel NF-κB modulators and therapeutic targets. Artificial intelligence (AI) and machine learning are also being integrated to analyze large-scale NF-κB datasets, enabling the prediction of transcriptional outputs, signaling bottlenecks, and disease-relevant signatures.

Together, systems-level analyses and next-generation experimental tools are reshaping the landscape of NF-κB research, offering unprecedented insights into its complex regulation and therapeutic potential.

Conclusion

NF-κB is a family of proteins that becomes active when the body experiences stress or encounters infectious agents. This protein group is regulated through numerous control mechanisms, providing several opportunities to finely adjust its activation. Given NF-κB’s involvement in a wide range of physiological and pathological processes, achieving proper regulation of its activity in both health and disease presents a significant challenge in pharmacology. Fortunately, the pharmaceutical field now has access to an expanding array of tools-including antibodies, small molecules, antisense RNAs, and other targeted therapies-that can be applied with impressive specificity in various contexts. However, these diverse treatment options often come with high costs and are produced by competing companies, complicating the design of effective treatment protocols for physicians. Over time, as patents expire and prices potentially decrease, we can look forward to a future where conscientious physicians have greater flexibility to develop treatment plans that incorporate multiple therapeutic approaches.

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Acknowledgements

The NF-κB field encompasses a vast and dynamic body of research that spans decades, organisms, and scientific disciplines. In this review, we have focused primarily on the fundamental principles of NF-κB signaling as established through historic and mechanistic studies in mammalian systems. We acknowledge that this necessarily limits the breadth of our coverage and does not encompass equally important discoveries made in non-mammalian organisms, including seminal findings in invertebrates such as Drosophila and C. elegans that have shaped our understanding of innate immunity and NF-κB-like pathways.

Due to space constraints and the expansive nature of the literature, we regret that we could not cite all original research articles and contributions in the field. We extend our sincere apologies to our colleagues whose important work could not be referenced directly in this manuscript.

Authors’ contributions

A.H. is mainly involved in writing Sections 3, 4 and 5; G.C. is mainly involved in writing Sections 1, 2, 6 and 7; and D.B. is mainly involved in writing Abstract and Conclusion. All authors contribute to the editing of the entire manuscript.

Funding

This work was supported by US National Institute of Health funds (R01AI173214 to A.H., R01AI185026 to G.C.) http://dx.doi.org/10.13039/100000002 .

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The corresponding author Genhong Cheng is Deputy Editor of the journal Immunity & Inflammation. However, he was not involved in the peer-review or decision-making process for this manuscript. The authors declare no other competing interests.

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