Nuclear Factor-kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways (NF-κB and MAPK pathways)

The Nuclear Factor-kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways are fundamental intracellular networks that coordinate cellular responses to external stimuli such as cytokines, growth factors, and environmental stressors (Zhang et al., 2017, PubMed; Morrison, 2012, CSH Perspect Biol). The NF-κB pathway is a central regulator of the immune response and cell survival, primarily functioning through the nuclear translocation of transcription factors that activate pro-inflammatory and anti-apoptotic genes (Oeckinghaus & Ghosh, 2009, Cold Spring Harb Perspect Biol). The MAPK pathways, comprising the ERK, JNK, and p38 cascades, involve a series of protein kinase phosphorylation events that control cell proliferation, differentiation, and apoptosis (Sun et al., 2015, Exp Mol Med). Aberrant activation of these pathways is a hallmark of many human pathologies, including chronic inflammatory disorders and various malignancies, where they contribute to uncontrolled tumor growth, metastasis, and evasion of the immune system (Dhillon et al., 2007, Oncogene). Because of their pivotal roles in disease progression, individual components within these pathways—such as IκB kinase (IKK), MEK1/2, and p38 MAPK—serve as high-priority therapeutic targets for small-molecule inhibitors and biologics (Kyriakis & Avruch, 2012, Physiol Rev). However, the extensive crosstalk between these pathways and their essential roles in normal physiology present significant challenges for achieving therapeutic selectivity and managing systemic toxicity.

Other names

NF-kappaB signaling pathwayMitogen-activated protein kinase signaling pathwayStress-activated protein kinase (SAPK) pathwaysPro-inflammatory signaling cascadesERK/JNK/p38 signaling pathways

Drugs targeting these pathways typically act as small-molecule inhibitors of specific kinases (e.g., MEK, p38, IKK) to block phosphorylation cascades, or inhibit the proteasome to prevent the degradation of inhibitory proteins like IκB, thereby preventing the nuclear translocation of transcription factors (Taniguchi & Karin, 2018, Nat Rev Immunol).