Review Article UNLOCKING THE THERAPEUTIC POTENTIAL: EXPLORING NF-κB AS A VIABLE TARGET FOR DIVERSE PHARMACOLOGICAL APPROACHES AJEET PAL SINGH 1,2* , ASHISH KUMAR SHARMA 1 , THAKUR GURJEET SINGH 3 1 NIMS Institute of Pharmacy, NIMS University, Jaipur-303121, Rajasthan, India and St. Soldier Institute of Pharmacy, Jalandhar-144011, Punjab, India. 2 NIMS Institute of Pharmacy, NIMS University, Jaipur-303121, Rajasthan, India. 3 Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India * Corresponding author: Ajeet Pal Singh; * Email: ajeetakarpuria@gmail.com Received: 30 Sep 2023, Revised and Accepted: 01 May 2024 ABSTRACT NF-κB is a vital transcription factor that responds to diverse stimuli like cytokines, infections, and stress. It forms different dimers, binds to specific DNA sequences, and regulates gene expression. It operates through two pathways: canonical (for inflammation and immunity) and non-canonical (for specific processes). These pathways tightly control activity of NF-κB and impacting gene expression. Aberrant NF-κB activation is linked to cancer and other diseases, making it a potential therapeutic target. This review explores the role of NF-κB in disease and its therapeutic potential in various conditions. Intricate signal transduction processes lead to NF-κB activation by phosphorylating IκB proteins, allowing NF-κB dimers to enter the nucleus and influence gene expression. This dynamic regulation involves co-activators and interactions with other transcription factors, shaping complex gene expression programs. Understanding the multifaceted functions off NF-κB is crucial as its deregulation is associated with a range of diseases, including cancer, autoimmune disorders, and inflammatory conditions. Exploring recent studies offers insights into potential therapeutic strategies aimed at modulating NF-κB activity to restore health and combat various pathological conditions. This Comprehensive review is based on the role of NF-κB in disease pathogenesis and therapeutic implications. Keywords: NF-κB, Canonical pathway, Non-canonical pathway, Autoimmune disorder and Inflammatory conditions © 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijpps.2024v16i6.49530 Journal homepage: https://innovareacademics.in/journals/index.php/ijpps INTRODUCTION NF-κB, denoted as the nuclear factor kappa-light-chain-enhancer of activated B cells, represents a pivotal transcription factor that becomes active in response to various stimuli, including cytokines, viral infections, and cellular stressors like hypoxia [1]. The intricate NF-κB network comprises a quintet of protein monomers, namely p65/RelA, RelB, cRel, p50, and p52. These monomers possess the ability to join forces, forming either identical or mixed dimers and exhibiting diverse affinities towards DNA binding [2]. Upon receiving external signals, cells undergo signal transduction processes that culminate in the phosphorylation of IκB, facilitating the release and nuclear translocation of NF-κB heterodimers to regulate gene expression [3]. The NF-κB family of transcription factors controls gene transcription by binding to specific DNA response elements in promoters or enhancers. These response elements, called B sites or B DNA, share a common consensus sequence. While the consensus sequence is well- defined, NF-κB dimers can also bind to DNA sequences that deviate from this consensus. X-ray crystal structures have provided insights into the molecular basis of target selection in vitro. However, in vivo, NF-κB dimers face additional challenges in selectively binding to DNA due to the complex chromatin environment [4]. NF-κB regulates gene expression through two distinct pathways: canonical and non-canonical. The canonical pathway responds to external stimuli and is linked to inflammation, immune response, cell processes, and survival. Activation of the canonical pathway relies on phosphorylation-dependent activation of the IKKs complex. In contrast, the non-canonical NF-κB pathway is selectively activated by a limited number of TNF superfamily receptors, suggesting a more specialized role for this branch of the pathway in biological processes [5]. The tightly orchestrated pathways in place exert stringent control over the levels and dynamics of the transcriptionally active NF-κB dimer repertoire, both in a constitutive manner and in response to external stimuli. Consequently, these pathways govern extensive programs of gene expression by engaging co-activators or collaborating with other transcription factors. The activation pathways employ multiple mechanisms to effectively modulate NF-κB activity, encompassing the degradation of IκB inhibitor proteins, the processing of NF-κB precursor proteins, and the expression of NF-κB monomer proteins [2]. Excessive stimulation and overactive engagement of the NF-κB pathway significantly propel the relentless advancement of cancer, thereby presenting a grave and formidable menace to the well-being of humanity [6]. When the body faces an infection or injury, NF-κB gets activated and helps initiate the body's defense mechanisms. It triggers the production of molecules like cytokines, which are important for the immune response. However, if NF-κB becomes overactive or stays activated for a long time, it can lead to chronic inflammation and contribute to various health issues, including cancer. It was observed that ZnO-NP (zinc oxide nanoparticles) has a strong binding affinity with NF-κB, suggesting a potential interaction between these nanoparticles and the protein. This interaction may have implications for the regulation of inflammation and immune responses in the body [7]. The current review focuses on the role of NF-κB in disease induction as well as healing. Moreover, this article includes the recent studies held on NF-κB. Search methodology This review encompasses information collected from peer-reviewed journal articles sourced from databases like PubMed, Google Scholar, Nature Journal, and Science Direct, covering the period between 1998 and 2023. Keywords such as "NF-κB," "Family of NF-κB," "Pathways," "Clinical Uses," "Role of NF-κB in Disease," "Therapeutic Applications of NF-κB” and “Recent Studies on NF-κB” were employed during the search process. The review offers a comprehensive understanding of the multifaceted functions of NF- κB and the latest insights into its potential therapeutic applications. Additionally, it delves into the structure and composition of the NF- κB family, shedding light on the complexities of its DNA binding and interaction with other cellular components. International Journal of Pharmacy and Pharmaceutical Sciences Print ISSN: 2656-0097 | Online ISSN: 0975-1491 Vol 16, Issue 6, 2024