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

The NF-κB and p38 MAPK inflammatory pathways are central signaling cascades that coordinate the cellular response to pro-inflammatory cytokines, pathogens, and environmental stressors [1, 16]. NF-κB functions as a rapid-acting transcription factor that, once released from its inhibitory IκB proteins, translocates to the nucleus to induce the expression of genes critical for innate and adaptive immunity [10, 12]. p38 MAPK is a serine/threonine kinase that responds to similar stimuli by phosphorylating a wide array of substrates, thereby regulating the production and activity of inflammatory mediators like TNF-α and IL-6 [2, 3]. These two pathways are intricately linked, with p38 MAPK often modulating the transcriptional activity of NF-κB or the stability of its target mRNAs, creating a synergistic axis for inflammatory gene expression [6, 13, 22]. Chronic overactivation of the NF-κB/p38 MAPK axis is implicated in the pathogenesis of numerous inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease [1, 3, 6]. In oncology, these pathways contribute to tumor progression, survival, and resistance to chemotherapy by promoting an inflammatory microenvironment and inhibiting apoptosis [4, 11, 19]. Therapeutic strategies targeting this axis include small-molecule inhibitors of p38 MAPK and agents that block NF-κB activation, such as proteasome inhibitors or IKK complex antagonists [1, 18, 20]. Despite their therapeutic potential, drug development has faced significant hurdles, including systemic toxicity, hepatotoxicity, and the challenge of achieving sustained efficacy without compromising essential immune functions [1, 3, 20].

Other names

NF-kappaB/p38 MAPK axisp38-NF-kappaB signaling pathwayStress-activated protein kinase pathwaysPro-inflammatory signaling pathways

Inhibition of p38 mitogen-activated protein kinase activity and inhibition of the NF-κB signaling cascade, typically through IKK inhibition or proteasome blockade.