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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\u2010canonical NF\u2010\u03baB signalling is well\u2010established, translating this extensive knowledge into clinically viable therapeutics remains severely hindered by dose\u2010limiting systemic toxicities and complex pharmacokinetic liabilities. This review critically evaluates the transition of NF\u2010\u03baB 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\u2010depth analysis of next\u2010generation therapeutic interventions. We specifically dissect advanced molecular strategies, moving beyond conventional pharmacological inhibitors to emphasize nucleic acid\u2010based 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\u2010target effects. By mapping these cutting\u2010edge modalities, this review underscores the critical necessity of transitioning from broad\u2010spectrum inhibition toward context\u2010specific, precision\u2010engineered modulation of the NF\u2010\u03baB axis.<\/jats:p>","DOI":"10.1111\/jcmm.71229","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:11:10Z","timestamp":1780632670000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The\n                    <scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Signalling Pathway: Mechanisms, Consequences and Therapeutic Targets"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3700-2803","authenticated-orcid":false,"given":"Bherouz","family":"Pourdad","sequence":"first","affiliation":[{"name":"Medical Biotechnology Department, Mashhad Medical School Mashhad 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