NEMO/IKKγ: Emerging player in the NF-κB pathway and potential therapeutic target in inflammation.

Inflammation is marked by the influx of mononuclear innate immune cells from systemic to local tissue. The activation of the NF-κB pathway is a major cause of immune cell infiltration. Although external stimuli can activate the NF-κB pathway, the downstream canonical cascade is mostly controlled by the IKK complex. This complex is formed by three kinase components, IKKβ, IKKα, and NEMO (the NF-κB essential modulator). NEMO is critical in controlling the scaffolding of the IKK complex. Scaffolding can activate the IKK complex, causing autophosphorylation of IKKβ and proteasomal destruction of IκBα, an inhibitory molecule. This leads to the translocation of NF-κB dimers (p55 and p60) into the nucleus, which act as transcription factors for proinflammatory gene activation. While numerous small-molecule inhibitors targeting IKKβ have been demonstrated to have preclinical efficacy in cancer and inflammatory disorders models, their clinical translation has been limited due to safety concerns and off-target effects. For this reason, an alternative yet more selective therapeutic intervention, i.e., NEMO, was introduced owing to its success in modulating NF-κB signalling without compromising the safety. In this narrative review, we critically assess current understanding of NEMO’s role in canonical NF-κB signalling, including its mechanisms of activation and regulatory function in inflammation. We further explore the therapeutic potential of NEMO inhibition, reviewing relevant small molecular drugs, their limitations, and future direction for drug development in this context. Our narrative aims to provide a comprehensive framework for harnessing NEMO as a druggable node in the NF-κB pathway with translational relevance for inflammatory diseases.Clinical Trial Number: Not applicable.