ISG15 is an interferon-stimulated ubiquitin-like protein that serves as a central effector of innate immunity against viral infection 1. The protein functions through two mechanisms: direct conjugation to target proteins via enzymatic ISGylation, and action as a secreted immunomodulatory factor. ISGylation modifies diverse targets including the viral sensor IFIH1/MDA5, promoting its oligomerization and triggering antiviral immunity against coronaviruses, flaviviruses, and picornaviruses. ISG15 exhibits broad antiviral activity by restricting HIV-1 and Ebola virus through disruption of viral budding, and inhibiting influenza A virus replication. Secreted ISG15 acts as a chemotactic factor for neutrophils and induces interferon-gamma production through integrin-mediated signaling, playing an essential role in antimycobacterial immunity. Beyond antiviral defense, ISG15 displays context-dependent roles in disease. In acute kidney injury, ISG15 accelerates both initial injury and subsequent progression to chr1 kidney disease by promoting TGFβR1 ISGylation 2. In cardiac disease, pressure overload upregulates ISG15 through type I interferon signaling, facilitating adverse ventricular remodeling by ISGylating filamin-C and disrupting cardiomyocyte protein turnover 3. Conversely, during Coxsackievirus B3 infection, ISG15 protects cardiac function by blocking glycolysis and preserving mitochondrial energy production 4. In Alzheimer disease, elevated ISG15 impairs autophagic flux by inhibiting HDAC6, exacerbating tau accumulation 5. ISG15 and ISGylation function as both diagnostic/prognostic biomarkers and therapeutic targets across multiple disease contexts 6.