IKK-β inhibition as a precision therapeutic approach to disrupt the NF-κB neuroinflammatory cascade in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder hallmarked by dopaminergic neuronal loss and pathological α-synuclein accumulation. Increasing evidence positions neuroinflammation as a central driver of disease initiation and progression, orchestrating maladaptive glial responses that amplify neuronal vulnerability. At the heart of these inflammatory cascades lies the NF-κB signaling pathway, a master regulator of immune and stress responses in neurons and glia. While basal NF-κB activity supports neuronal homeostasis, chronic dysregulation in PD perpetuates microglial activation, oxidative stress, and α-synuclein-induced neurotoxicity. IκB kinase-β (IKK-β), a critical upstream regulator of NF-κB, has emerged as a promising therapeutic target, with preclinical studies demonstrating that its modulation attenuates neuroinflammatory signaling and preserves neuronal integrity. This review consolidates current mechanistic insights into NF-κB dysregulation in PD, highlighting the interplay between glial activation, mitochondrial dysfunction, and progressive neurodegeneration. We discuss emerging strategies to target IKK-β, encompassing pharmacological inhibitors and genetic approaches, alongside considerations for central nervous system specificity and translational feasibility. By integrating molecular, cellular, and preclinical perspectives, we propose a framework in which precise modulation of NF-κB signaling through IKK-β offers a mechanistically informed avenue to counteract neuroinflammation and potentially modify PD pathology.