Fig. 1

The canonical and non-canonical pathways of the NF-κB signaling pathway. This signaling pathway comprises three distinct routes: the canonical, non-canonical pathways and atypical pathway. In the canonical pathway, Toll-like receptors (TLRs), tumor necrosis factor receptors (TNFRs), and interleukin-1 receptors (IL-1Rs) are activated, leading to the phosphorylation and subsequent degradation of the inhibitory protein IκB. As a result, NF-κB is liberated from the complex with IκB and translocates to the nucleus. Conversely, the non-canonical pathway relies on the activation of the NF-κB2 (p100)/RelB complex by specific receptors such as B-cell activating factor receptor (BAFFR), CD40, and receptor activator of nuclear factor κB (RANK). This activation triggers a cascade of events, including the phosphorylation of NF-κB-inducing kinase (NIK), which in turn phosphorylates IKKα. Consequently, the p52-RelB heterodimer is activated and translocates to the nucleus. The activation of NF-κB signaling pathway exerts regulatory effects on various cellular processes by controlling the expression of cytokines, chemokines, and other genes. Several “atypical” pathways have been described, including radiation-induced NF-κB activation. NF-κB activation follows an atypical pathway, involving distinct phosphorylation events such as Tyr42 phosphorylation by Syk or Src family kinases, triggered by various stimuli. This leads to IκBα dissociation from the RelA/p50 dimer without proteasomal degradation. In the PEST domain, CKII phosphorylates IκBα at Ser293, promoting calpain-mediated degradation