In the last 20 years the knowledge about the NF-kB/IKK role in the most important cellular processes such as inflammation, tumorigenesis and cancer progression has been very impressive. In particular, it has become clear that such processes are closely linked and interconnected [
1‐
3]. In mammals, the NF-kB complex consists of five monomeric proteins (p65 / RelA, RelB, cRel, p50 and p52) forming homodimers or hetero-dimers that bind with different affinity to DNA. The “canonical” regulation of NF-kB is intricate and mediated by a protein kinase complex, consisting of a NEMO scaffold / adapter protein (IKKγ) and two IκB kinases (IKKα and IKKβ); for this reason, it is also called NEMO dependent. IKKα is an 85 kDa protein, initially identified as a serine-threonine with unknown function. IKKβ is an IKKα-related 87 kDa protein. IKKγ (50–52 kDa) contains several regions with spiral wound N-terminal helical motifs, an LZ and a C-terminal Zn-finger. IKK kinases are activated through the phosphorylation of serines located in an activation T-loop with a complicated mechanism which has not been fully understood yet. This phosphorylation probably involves a conformational change, responsible for the activation of kinases. In condition of cellular homeostasis, NF-kB is kept inactive in the cytoplasm through interaction with inhibitory molecules belonging to the IkB family [
4,
5]. When IkB is phosphorylated and polyubiquitinated, it is degraded by proteasome, so allowing the release of NF-kB which can translocate into the nucleus and activate the transcription of its target genes, binding to DNA sequences called response elements (RE). The formation of the DNA / NF-kB complex involves other proteins as coactivators, thus allowing the activation and transcription of target genes. Moreover, the IKK complex has a key role as signaling hub for NF-kB activation and as an interface with other signaling cascade, such as mTOR and MAPK pathways [
6,
7]. Several studies have pointed out that IKKβ is involved in promoting tumorigenicity through the inhibition of tumor suppressors by phosphorylation; therefore, IKKβ is considered an oncogenic kinase [
5,
8]. Recently, it was highlighted that IKK complex interacts with the Keap1 protein, the master repressor of Nrf2 [
9‐
12]. KEAP1 and NRF2 are the two key genes that regulate the oxidative stress pathway. Nuclear factor erythroid 2–related factor 2 (NFE2L2 or NRF2) is considered as one of the major antioxidant transcription factors against oxidative and electrophilic stress [
13,
14]. When cells are exposed to oxidative stress, KEAP1 undergoes conformation changes and dissociation from NRF2 [
15]. Nrf2, released from the Keap1–Nrf2 complex, translocates from the cytoplasm into the nucleus and activates the expression of related antioxidant genes [
16]. Moreover, Keap1 works as a E3 ligase of IKKβ, since it has an ETGE-Motif-NQE36TGE39- homologous to the one present in the Nrf2 protein, so KEAP1 is considered as a IKKβ interacting protein [
17] and mutations or alterations in Keap1 gene are correlated with cancer or a deeply altered cell stress response [
18]. A recent study [
9,
10] carried out in RAW264.7 cells shows that IKK kinase is activated by canonic LPS-signalling when Keap1 is functionally active. Keap1 is a key protein in the interaction between inflammation and oxidative stress. Interestingly, it emerges that Hsp90 and KEAP1 interact upon heat shock, leading to the activation of NRF2 [
19], and that the environmental redox changes can induce heat shock genes [
20,
21]. Therefore, in this paper we analyze the crosstalk between IKK kinase, HSP90 and anti-inflammatory response mediated by COX2 and Heme Oxygenase-1 (HO1) enzymes. More precisely, we induce the inhibition of IKK phosphorylation by using BMS-345541 in the cell line A549 mutated in Keap1 allele [
22] in order to observe the effects on the underlying molecular mechanism.