TANK-binding kinase 1–Nuclear factor kappa-light-chain-enhancer of activated B cells–p38 mitogen-activated protein kinase signaling pathway (TBK1–NF-κB–p38 signaling)

The TBK1–NF-κB–p38 signaling axis is a multi-protein signaling network that plays a central role in the regulation of innate immunity and inflammatory responses. TANK-binding kinase 1 (TBK1) acts as a key integrator of signals from various pattern recognition receptors, including Toll-like receptors (TLRs) and the cGAS-STING pathway (UniProt Q9UHD2). Upon activation, TBK1 triggers a cascade that leads to the activation of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the p38 mitogen-activated protein kinase (MAPK) pathways (PubMed: 31430478). This coordinated activation results in the production of pro-inflammatory cytokines and type I interferons, which are vital for host defense but can lead to chronic inflammatory diseases and autoimmune disorders if dysregulated. In oncology, this signaling axis is frequently exploited by tumor cells to promote survival, metastasis, and resistance to therapy (PubMed: 30233454). Therapeutic strategies targeting this pathway involve small molecule inhibitors of TBK1, such as Amlexanox, or p38 MAPK inhibitors like Ralimetinib, which are being evaluated for their ability to modulate immune responses and improve outcomes in cancer and inflammatory conditions (PubMed: 23403768).

Other names

TBK1/NF-kappaB/p38 MAPK axisTBK1-mediated inflammatory signalingTBK1-NFkB-p38 MAPK cascadeTANK-binding kinase 1 signaling pathway

The pathway is targeted through the inhibition of TBK1 kinase activity, the inhibition of p38 MAPK phosphorylation, or the modulation of NF-κB nuclear translocation, thereby preventing the transcription of pro-inflammatory and pro-survival genes.