p38 mitogen-activated protein kinase and nuclear factor-kappa B signaling pathway (p38 MAPK/NF-κB)

The p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway is a vital intracellular network that coordinates cellular responses to environmental stressors, pro-inflammatory cytokines, and pathogens [4, 9]. This pathway involves the activation of four p38 MAPK isoforms (α, β, γ, and δ), which subsequently modulate the activity of the NF-κB transcription factor complex, often through intermediate kinases like mitogen- and stress-activated protein kinase 1 (MSK1) [6, 8]. Activation of this axis leads to the phosphorylation and acetylation of the p65 (RelA) subunit of NF-κB, significantly enhancing its transcriptional potency for genes encoding pro-inflammatory cytokines such as TNF-α and IL-1β [5, 16]. Dysregulation of this crosstalk is a hallmark of chronic inflammatory diseases, autoimmune disorders, and various cancers, where it promotes tumor survival and resistance to therapy [1, 2]. Consequently, the pathway has been a focal point for therapeutic intervention, primarily through the development of small-molecule p38 inhibitors and agents that disrupt the IKK-dependent activation of NF-κB [10, 16].

Other names

p38 MAPK-NF-kappaB axisp38 mitogen-activated protein kinase/nuclear factor-kappa B signaling cascadep38/NF-kB pathwayCytokine suppressive drug binding protein (CSBP) pathway

ATP-competitive inhibition of p38 MAPK phosphorylation, inhibition of IκB kinase (IKK) complex activity, and stabilization of IκB-α to prevent NF-κB nuclear translocation and transcriptional activity [2, 16].