The NF-κB Signalling Pathway: Mechanisms, Consequences and Therapeutic Targets

Nuclear Factor-kappa B (NF-κB) is a master transcriptional regulator orchestrating critical cellular processes, predominantly immunity and inflammation. However, its aberrant constitutive activation has emerged as a unifying pathogenetic hallmark across diverse malignancies, autoimmune disorders, and chronic inflammatory diseases. While the fundamental biology of canonical and non-canonical NF-κB signalling is well-established, translating this extensive knowledge into clinically viable therapeutics remains severely hindered by dose-limiting systemic toxicities and complex pharmacokinetic liabilities. This review critically evaluates the transition of NF-κB from a basic biological paradigm to a highly challenging yet promising therapeutic target. After a streamlined synthesis of its signalling dynamics and pathological implications across various disease states, the core focus of this report shifts to an in-depth analysis of next-generation therapeutic interventions. We specifically dissect advanced molecular strategies, moving beyond conventional pharmacological inhibitors to emphasize nucleic acid-based therapies, including decoy oligodeoxynucleotides (ODNs), peptide nucleic acids (PNAs), and locked nucleic acids (LNAs). Furthermore, we critically address current translational bottlenecks, highlighting the pivotal role of lipid nanoparticle (LNP) transporters and smart drug delivery systems in overcoming off-target effects. By mapping these cutting-edge modalities, this review underscores the critical necessity of transitioning from broad-spectrum inhibition toward context-specific, precision-engineered modulation of the NF-κB axis.