NFKB1, encoding the transcription factor precursor p105 which can be processed to p50, is one of the five subunits of NF-κB. The NF-κB signaling pathway, in which NFKB1 is involved, governs key cellular processes like immune responses and apoptosis, and is crucial for cellular homeostasis [2,5]. Mouse models with Nfkb1 knockout (Nfkb1-/-) have been valuable in in vivo studies to understand its functions [5].

In humans, heterozygous NFKB1 mutations are associated with a range of immunologic phenotypes. These include primary immunodeficiency features such as hypogammaglobulinemia, reduced switched memory B cells, and respiratory and gastrointestinal infections. However, there is also a high frequency of autoimmunity, lymphoproliferation, non-infectious enteropathy, opportunistic infections, autoinflammation, and malignancy, classifying NF-κB1-related disease as an inborn error of immunity with immune dysregulation [1]. Truncating monoallelic loss-of-function variants of NFKB1 can lead to combined NLRP3 inflammasome activation and type I interferon signaling, predisposing patients to necrotizing fasciitis [3]. Regarding cancer, the role of NFKB1 is complex, sometimes driving cancer progression and in other cases acting as a tumor-suppressor. A meta-analysis showed that the NFKB1-94ins/delATTG polymorphism was associated with a decreased risk of overall cancer [4]. Bioinformatics analysis also indicates its association with cancer susceptibility, prognosis, and drug sensitivity [6].

In summary, NFKB1 is an important regulator of the NF-κB signaling pathway, with its functions spanning immune responses, apoptosis, and cellular homeostasis. Studies using Nfkb1 knockout mouse models have provided insights into its role in inflammation, cancer, and other disease conditions, highlighting its potential as a target for therapeutic strategies in inflammatory diseases and cancer [5].

References:

1. Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Warnatz, Klaus, Grimbacher, Bodo. 2020. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. In The Journal of allergy and clinical immunology, 146, 901-911. doi:10.1016/j.jaci.2019.11.051. https://pubmed.ncbi.nlm.nih.gov/32278790/

2. Concetti, Julia, Wilson, Caroline L. 2018. NFKB1 and Cancer: Friend or Foe? In Cells, 7, . doi:10.3390/cells7090133. https://pubmed.ncbi.nlm.nih.gov/30205516/

3. Nurmi, Katariina, Silventoinen, Kristiina, Keskitalo, Salla, Seppänen, Mikko R J, Eklund, Kari K. 2024. Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis. In Cell reports. Medicine, 5, 101503. doi:10.1016/j.xcrm.2024.101503. https://pubmed.ncbi.nlm.nih.gov/38593810/

4. Fu, Wen, Zhuo, Zhen-Jian, Chen, Yung-Chang, He, Jing, Liu, Guo-Chang. . NFKB1 -94insertion/deletion ATTG polymorphism and cancer risk: Evidence from 50 case-control studies. In Oncotarget, 8, 9806-9822. doi:10.18632/oncotarget.14190. https://pubmed.ncbi.nlm.nih.gov/28039461/

5. Cartwright, Tyrell, Perkins, Neil D, L Wilson, Caroline. 2016. NFKB1: a suppressor of inflammation, ageing and cancer. In The FEBS journal, 283, 1812-22. doi:10.1111/febs.13627. https://pubmed.ncbi.nlm.nih.gov/26663363/

6. Song, Zixuan, Feng, Zheng, Wang, Xiaoxue, Li, Jingying, Zhang, Dandan. 2025. NFKB1 as a key player in Tumor biology: from mechanisms to therapeutic implications. In Cell biology and toxicology, 41, 29. doi:10.1007/s10565-024-09974-2. https://pubmed.ncbi.nlm.nih.gov/39797972/