IKKα signalling at the crossroads of development, disease and drug discovery

IκB kinase alpha (IKKα) is a central regulator of non-canonical NF-κB signalling and contributes modestly to canonical NF-κB signalling, both of which mediate well-established aspects of immune function and inflammation. Emerging evidence now indicates that IKKα also performs a wide range of atypical functions, influencing NF-κB indirectly or acting through mechanisms independent of either NF-κB pathway. Several IKKα substrates have been identified outwith these classical signalling routes, and a recently described truncated isoform, p45-IKKα, has further expanded its known roles. This review examines how IKKα, through these diverse signalling modalities, contributes to disease processes including inflammatory disorders and cancer. Particular attention is given to both NF-κB-dependent and NF-κB-independent mechanisms that shape disease development, tumor biology, and ageing. Recent studies have also linked IKKα gene variants (CHUK) to altered IKKα function and patient outcomes, and advances in medicinal chemistry combined with early pharmacological testing have produced the first selective inhibitors of this kinase. Together, this review provides an updated and integrated overview of the complex biology of IKKα and its emerging potential as a therapeutic target.