Interferon-Induced Protein 6 (IFI6): Biological Functions, Molecular Mechanisms and Pathological Roles in Human Diseases

Interferon (IFN)-induced protein 6 (IFI6) is an important member of the IFN-stimulated gene (ISG) family, mainly enriched in the inner mitochondrial membrane and endoplasmic reticulum (ER). It plays significant roles in anti-apoptosis, immune regulation, maintenance of mitochondrial homeostasis, antiviral defense, and promotion of tumor progression. At the molecular mechanism level, IFI6 inhibits mitochondrial membrane depolarization, cytochrome c release, and caspase activation. It also regulates the B-cell lymphoma 2 (Bcl-2)/Bcl-2 interacting mediator of cell death (Bim) expression balance, activates the janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathways, and inhibits the degradation of ferroptosis-related proteins solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby enhancing cell survival and proliferation through multiple pathways. In terms of immune regulation, IFI6 also affects immune cells (such as T/B cells, etc.) and the tumor microenvironment. IFI6 regulates mitochondrial reactive oxygen species (mtROS) and mitochondrial calcium homeostasis, influencing respiratory chain assembly and metabolism. In terms of virus regulation, IFI6 may inhibit the replication of multiple viruses (such as hepatitis B virus (HBV), hepatitis C virus (HCV), SARS-CoV-2, etc.) by inhibiting flavivirus-induced ER invagination, interfering with retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathways, and inhibiting epidermal growth factor receptor (EGFR) kinase activity. In addition, IFI6 is highly expressed in autoimmune diseases and malignant tumors and is associated with proliferation, metastasis, and poor prognosis. In this review, we aim to highlight IFI6 as a potential key target in disease diagnosis and treatment.