Rel, also known as c-Rel, is a member of the Rel/NF-κB transcription factor family. It plays a crucial role in regulating a variety of genes, especially those encoding proteins important for the immune system, and is involved in B-cell activation, proliferation, and survival [5,6]. Aberrant constitutive activation of Rel/NF-κB is a hallmark of numerous cancers, and among the five Rel family members, c-Rel has the strongest direct links to tumorigenesis [1]. Genetic models, such as gene knockout mice, have been instrumental in studying its functions.

In gene knockout studies, global (Rel-/-) and epithelial specific (RelAlb) c-Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild-type controls 30 weeks after N-diethylnitrosamine injury, indicating that c-Rel signaling is important for preventing hepatocellular carcinoma (HCC) initiation after genotoxic injury [2]. In another study, c-Rel-deficient (c-Rel-/-) mice presented a significantly reduced response to papain-and IL-33-induced lung inflammation, showing that c-Rel is critical for the function of group 2 innate lymphoid cells (ILC2s) in the lung [3]. Also, c-Rel deficiency protected mice from imiquimod-induced psoriatic lesions by disrupting activating NF-κB dimers and inhibiting the expression of IL-1β and IL-6 [4].

In conclusion, c-Rel is a key regulator in multiple biological processes, including immune-related functions and cancer-related processes. Gene knockout mouse models have been essential in revealing its role in diseases such as HCC, lung inflammation, and psoriasis, providing valuable insights into the underlying molecular mechanisms and potential therapeutic targets.