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

The NF-κB and MAPK signaling pathways are two fundamental, interconnected intracellular networks that orchestrate the cellular response to inflammatory stimuli, stress, and growth factors. NF-κB is a family of inducible transcription factors that regulate the expression of genes involved in innate and adaptive immune responses, cell survival, and inflammation (Liu et al., 2017, Signal Transduct Target Ther). The MAPK pathways comprise a cascade of protein kinases—specifically ERK, JNK, and p38—that convert extracellular signals into various cellular outputs, including proliferation and apoptosis (Zhang & Liu, 2002, Cell Res). These pathways often act in concert; for instance, many pro-inflammatory cytokines like TNF-α and IL-1 simultaneously activate both NF-κB and MAPK cascades to amplify the inflammatory response (Kyriakis & Avruch, 2012, Physiol Rev). Chronic overactivation of these pathways is a primary driver in the pathogenesis of autoimmune disorders, chronic inflammatory diseases, and various malignancies where they promote tumor cell evasion of apoptosis (Oeckinghaus & Ghosh, 2009, Cold Spring Harb Perspect Biol). Consequently, they are major focal points for drug development, with therapeutic strategies ranging from small molecule kinase inhibitors to biologics that block upstream receptors. However, because these pathways are essential for normal homeostasis and host defense, therapeutic targeting faces significant challenges regarding systemic toxicity and the risk of profound immunosuppression.

Other names

NF-kappaB and MAPK pathwaysPro-inflammatory signaling networkNFKB-MAPK axisNF-kappaB/MAPK inflammatory signaling

Inhibition of the IκB kinase (IKK) complex to prevent the phosphorylation and degradation of IκB, thereby sequestering NF-κB in the cytoplasm; or the inhibition of Mitogen-activated protein kinase kinases (MAPKK/MEK) and terminal MAP kinases (p38, JNK, ERK) to prevent the phosphorylation of downstream transcription factors and the subsequent expression of pro-inflammatory genes.