Ikbkb, also known as IKKβ (IkappaB kinase beta) or IKK2, is a key molecule in the signaling pathway to the transcription factor NF-κB. Its kinase activity phosphorylates IkappaB molecules, leading to their ubiquitination and proteasomal degradation, and subsequent release and activation of NF-κB. Many signaling pathways that activate NF-κB converge at the level of Ikbkb. NF-κB has diverse functions in regulating the immune system, cellular differentiation, survival, and proliferation. Ikbkb is thus crucial in acute and chronic inflammation, which is associated with various diseases, and also in cancer where NF-κB can act as a survival factor for malignant cells [7].

In Huntington's disease, Ikbkb can regulate endogenous S13 huntingtin phosphorylation via a non-canonical interferon regulatory factor3-mediated IKK pathway, reducing mutant huntingtin aggregation [1]. In a male infant with a heterozygous gain-of-function (GOF) Ikbkb variant, it was associated with autoimmunity and autoinflammation, showing increased basal levels of phosphorylation of IKKα/β and p65, and higher degradation of IkBα in transduced Jurkat cells [2]. In spinal nerve ligation (SNL) rats, delivering Ikbkb small interfering RNA (siRNA)-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles reduced neuropathic pain by inhibiting microglial activation [3]. In clear cell renal cell carcinoma (ccRCC), decreased Ikbkb expression was observed, and patients with upregulated Ikbkb protein expression had higher nuclear grade tumors and shorter survival [4]. In hepatocellular carcinoma (HCC), IKKβ phosphorylated and stabilized USP30, promoting lipogenesis and tumorigenesis [5]. In gliomagenesis, α-ketoglutarate-produced by GDH1 under low glucose-directly binds to and activates IKKβ and NF-κB signaling, promoting glucose uptake and tumor cell survival [6]. In osteoarthritis, decreased miR-214-3p activates the NF-κB signaling pathway and aggravates OA development through targeting Ikbkb [8].

In conclusion, Ikbkb is essential in the NF-κB signaling pathway and has a significant impact on various biological processes and disease conditions such as neurodegenerative diseases, autoimmune and autoinflammatory disorders, neuropathic pain, cancer, and osteoarthritis. Studies on Ikbkb, especially through functional models, help in understanding disease mechanisms and may provide potential therapeutic targets.