Irf3, short for Interferon Regulatory Factor 3, is a crucial transcription factor in the interferon regulatory factor family. It plays a vital role in human innate antiviral immune responses, especially as a principal early regulator of type I interferons (TI-IFNs) downstream of intracellular virus sensing. Signaling pathways involving kinases like IκB kinase epsilon (IKKε) and TANK-binding kinase-1 (TBK1), along with scaffold proteins such as TRAF family member-associated NF-κB activator (TANK), NF-κB-activating kinase-associated protein 1 (NAP1) and TANK-binding kinase 1-binding protein 1 (TBKBP1)/similar to NAP1 TBK1 adaptor (SINTBAD), are associated with its activation [1].

Genetic ablation of Irf3 in mice has shown significant implications. In AOM/DSS and Apcmin/+ models, Irf3-deficient mice are hyper-susceptible to intestinal tumor development, as Irf3 deficiency promotes intestinal epithelial cell proliferation by aberrantly activating the Wnt signaling pathway. Mechanically, resting-state Irf3 associates with active β-catenin in the cytoplasm, preventing its nuclear translocation and cell proliferation [2]. In the context of myocardial infarction, mice genetically deficient in Irf3 exhibit improved survival, with decreased cardiac expression of inflammatory cytokines, chemokines, and inflammatory cell infiltration, along with attenuated ventricular dilation and improved cardiac function. This indicates that ischemic cell death-induced activation of Irf3 and type I IFN production fuel a fatal response to myocardial infarction [3]. In the bile duct ligation model of obstructive cholestasis, Irf3 knockout (Irf3-/-) mice show significantly attenuated liver and kidney damage and fibrosis, with attenuated cell-death pathways and inflammatory responses [4].

In conclusion, Irf3 is essential in innate antiviral immunity and also plays roles in tumorigenesis, myocardial infarction, and cholestatic liver and kidney injury. Gene knockout mouse models have been instrumental in revealing these functions, providing valuable insights into the mechanisms of these diseases and potentially guiding the development of therapeutic strategies.