Nuclear factor kappa-light-chain-enhancer of activated B cells and Activator protein 1 signaling pathways (NF-κB/AP-1)

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator protein 1 (AP-1) signaling pathways are fundamental regulatory networks that coordinate the cellular response to inflammatory stimuli, stress, and pathogens [1, 6]. NF-κB and AP-1 are inducible transcription factors that often function cooperatively to drive the expression of a broad array of pro-inflammatory cytokines, chemokines, and adhesion molecules [5, 13]. Under physiological conditions, these pathways are tightly regulated to ensure a transient and appropriate immune response; however, their chronic or constitutive activation is a primary driver of autoimmune diseases, chronic inflammation, and various cancers [7, 15, 16]. In oncology, these pathways contribute to tumor cell survival, proliferation, and resistance to chemotherapy by upregulating anti-apoptotic genes [4, 7, 12]. Therapeutic targeting of these pathways has been a major focus in drug development, utilizing strategies such as IκB kinase (IKK) inhibition, proteasome blockade, and the use of glucocorticoids or biological agents that neutralize upstream triggers like TNF-α [3, 8, 12]. Despite their therapeutic potential, the essential role of NF-κB and AP-1 in normal tissue homeostasis and host defense presents significant challenges, as systemic inhibition can lead to profound immunosuppression and other on-target toxicities [12, 15, 17].

Other names

NF-κB / AP-1–related inflammatory pathwaysNF-kappaB/AP-1 axisNF-κB/AP-1 inflammatory signalingPro-inflammatory transcription factor pathwaysNF-κB and AP-1 pathways

The mechanism of action involves the inhibition of the IκB kinase (IKK) complex, which prevents the phosphorylation and subsequent proteasomal degradation of IκB proteins, thereby sequestering NF-κB in the cytoplasm [2, 3, 8]. For AP-1, drugs often target upstream mitogen-activated protein kinases (MAPKs) such as JNK and ERK to prevent the phosphorylation and activation of Jun and Fos subunits [5, 6, 14]. Additionally, glucocorticoids like dexamethasone act by inducing the expression of IκBα or through direct protein-protein interactions between the glucocorticoid receptor and the p65 or c-Jun subunits, leading to transcriptional repression [14, 15].