Nuclear factor kappa-light-chain-enhancer of activated B cells and Mitogen-activated protein kinase inflammatory signaling pathway (NF-κB/MAPK pathway)

The NF-κB/MAPK inflammatory signaling pathway is a complex regulatory network that integrates various extracellular signals to control the cellular response to stress, infection, and pro-inflammatory cytokines [6, 7]. It comprises two primary interconnected axes: the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and the Mitogen-Activated Protein Kinase (MAPK) pathway, which includes p38, JNK, and ERK cascades [2, 5]. NF-κB acts as a central transcription factor that, upon activation by the IKK complex, translocates to the nucleus to drive the expression of genes involved in immunity and cell survival [6, 8]. Simultaneously, the MAPK pathway regulates gene expression at both transcriptional and post-transcriptional levels, often serving as a critical threshold-setting mechanism for the production of inflammatory mediators like TNF-α and IL-6 [2, 7]. Dysregulation of this dual signaling axis is a hallmark of chronic inflammatory diseases, autoimmune disorders, and many cancers, where it promotes pathological inflammation and resistance to apoptosis [1, 4]. Therapeutic intervention typically involves small molecules or biologics that target specific nodes within the pathway, such as IKK inhibitors, proteasome inhibitors like bortezomib, or MAPK inhibitors like trametinib [8, 11]. However, because these pathways are essential for normal immune function and tissue homeostasis, systemic inhibition can lead to significant safety concerns, including immunosuppression and impaired wound healing [5, 8].

Other names

NF-kappaB/MAPK signalingNF-kB and MAPK pathwaysNF-κB/MAPK axisPro-inflammatory NF-κB/MAPK signaling

Inhibition of IκB kinase (IKK) complex activity, inhibition of mitogen-activated protein kinase kinases (MEK/MKK), prevention of IκB degradation via proteasome inhibition, and suppression of nuclear translocation of NF-κB dimers.