IFI44L is a type I interferon-stimulated gene (ISG) that functions as a critical mediator of antiviral and antibacterial immunity. During bacterial infection, it promotes macrophage differentiation and facilitates inflammatory cytokine secretion. IFI44L plays a role in controlling respiratory syncytial virus infection by reducing viral replication, though it exhibits low antiviral activity against hepatitis C virus 1. The protein also acts as a feedback regulator of interferon responses by negatively regulating IKBKB and IKBKE kinase activities through interaction with FKBP5. IFI44L is dysregulated in multiple disease contexts. In systemic lupus erythematosus and primary Sjögren's syndrome, IFI44L is among six shared hub genes elevated in both conditions and involved in interferon response pathways 2. Similarly, in systemic lupus erythematosus and rheumatoid arthritis, IFI44L promoter hypomethylation in peripheral blood mononuclear cells distinguishes patients from healthy controls with 81–84% sensitivity 3. In sepsis, IFI44L is identified as a PANoptosis-related signature gene associated with patient survival differences 4. In head and neck squamous cell carcinoma, IFI44L upregulation by ACSL4 promotes cell proliferation and invasiveness through enhanced interferon signaling 5. Genetically, IFI44L variants show protective effects: minor allele carriers in two population-based birth cohorts experienced lower rates of early-childhood respiratory tract infections and acute otitis media, with variant forms attenuating interferon pathway activation 6. These findings position IFI44L as both a key immune effector and a potential biomarker across autoimmune, infectious, and neoplastic diseases.