ISG15 (Interferon-Stimulated Gene 15) is a ubiquitin-like protein that plays dual roles in antiviral immunity and inflammatory regulation through both conjugated (ISGylation) and unconjugated forms 1. As an interferon-induced gene, ISG15 exhibits potent antiviral activity against DNA and RNA viruses including HIV-1, influenza A, and Ebola virus by disrupting viral budding, inhibiting viral protein function, and preventing virion assembly 1. The protein functions through ISGylation, a post-translational modification process where ISG15 is conjugated to target proteins via enzymatic cascades similar to ubiquitination 2. Key ISGylation targets include viral sensors like IFIH1/MDA5, promoting oligomerization and innate immune activation, and STING, where ISGylation at K289 is crucial for oligomerization and DNA sensing responses 3. However, ISG15 also serves as a negative regulator of interferon signaling by stabilizing USP18, preventing excessive IFN-α/β responses and autoinflammation 4. ISG15 deficiency in humans paradoxically causes enhanced interferon immunity and autoinflammatory symptoms rather than increased viral susceptibility 4. Beyond immunity, ISG15 contributes to pathological processes including cancer stem cell maintenance through mitochondrial regulation 5, adverse cardiac remodeling 6, and kidney injury progression 7, making it both a protective and pathogenic factor depending on context 2.