IFNAR1 is a cell surface receptor subunit that forms a heterodimeric complex with IFNAR2 to mediate type I interferon (IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ) signaling 1. Upon type I interferon binding, IFNAR1 and IFNAR2 are brought into proximity, allowing their associated kinases TYK2 (IFNAR1-bound) and JAK1 (IFNAR2-bound) to cross-phosphorylate and activate the JAK-STAT pathway 2. The activated kinases phosphorylate tyrosine residues on both receptor subunits and STAT transcription factors, enabling STAT nuclear translocation and expression of interferon-regulated genes that establish antiviral immunity 2. IFNAR1 can also function independently of IFNAR2 through non-JAK-STAT mechanisms. IFNAR1 deficiency has significant clinical consequences. Complete loss causes severe susceptibility to viral infections, particularly herpes simplex encephalitis in childhood 3. Dominant-negative IFNAR1 variants impair responses to IFN-α and IFN-ω while sparing IFN-β responses, increasing viral disease susceptibility 4. IFNAR1 is also implicated in non-infectious diseases; the BGN-TLR3-IFNAR1 axis promotes calcific aortic valve disease through type I interferon-driven osteoblast differentiation 5. Therapeutically, IFNAR1 blockade with anifrolumab successfully treats type-I interferonopathies (SAVI, CANDLE) by normalizing pathologic interferon signatures 6. Viruses including SARS-CoV-2 and enterovirus 71 antagonize immunity by triggering IFNAR1 degradation via secreted LRPAP1 7.