Nuclear factor NF-kappa-B p50 subunit (NFKB1) (NFKB1)

Nuclear factor NF-kappa-B p50 subunit (NFKB1) is a pivotal transcription factor that serves as a central regulator of the inflammatory response and immune system homeostasis (UniProt P19838). It is synthesized as a large 105 kDa precursor (p105) that undergoes proteasomal processing to generate the active p50 subunit, which typically forms heterodimers with p65 (RelA) to bind DNA response elements (Gupta et al., 2017, PMID: 28214311). In the context of inflammation, NFKB1 mediates the production of pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6, as well as the expression of Type I interferons like interferon-beta (Xia et al., 2004, PMID: 14568916). Andrographolide, a natural diterpenoid derived from Andrographis paniculata, acts as a potent inhibitor of this target by covalently binding to the Cys62 residue of the p50 subunit, thereby blocking its ability to bind to promoter regions of target genes (Xia et al., 2004, PMID: 14568916). This inhibition results in reduced systemic inflammation and is being explored for treating various inflammatory and autoimmune conditions, as well as modulating viral-induced cytokine storms (Lee et al., 2010, PMID: 20483371). Beyond its role in cytokine production, NFKB1 is involved in cell proliferation and apoptosis, making it a significant target in oncology research. Therapeutic strategies targeting NFKB1 aim to resolve chronic inflammation without compromising the host's overall immune competence. The specific covalent mechanism of andrographolide offers a unique approach to selective NF-kappa-B inhibition compared to broader kinase inhibitors.

Other names

NF-kappa-B1p105p50KBF1EBP-1Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1

Andrographolide inhibits the target by covalently binding to the Cys62 residue of the p50 subunit of NF-kappa-B, which prevents the complex from binding to DNA and initiating the transcription of pro-inflammatory cytokines and interferon-beta (Xia et al., 2004, PMID: 14568916).