ISG15/ISGylation in central nervous system diseases: molecular mechanisms and therapeutic targeting

Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier that plays a central role in innate immune signaling and antiviral defense. Increasing evidence indicates that ISG15 and its conjugation system (ISGylation) extend far beyond canonical antiviral activity to critically regulate neuroinflammatory responses in the central nervous system (CNS), contributing to the pathogenesis of viral encephalitis, neurodegenerative disorders, autoimmune demyelination, and certain neuropsychiatric conditions. Mechanistically, ISG15 functions in both conjugated and free forms, exerting context-dependent effects on key inflammatory pathways, including JAK-STAT , NF-κB, inflammasome activation, and cGAS-STING signaling. Through these coordinated actions, ISG15 acts as a molecular rheostat that fine-tunes neuroimmune responses, with outcomes determined by cell type, disease stage, and the balance between intracellular ISGylation and extracellular ISG15 signaling. This functional versatility underscores its translational relevance, as multiple components of the ISGylation machinery, such as the E1 enzyme UBE1L, the E2 enzyme UBE2L6, the E3 ligase HERC5, and the deISGylating Ubiquitin-specific protease 18 (USP18), representing emerging druggable nodes within interferon-driven networks. In this review, we summarize current insights into the molecular and cellular roles of ISG15 in neuroinflammation, highlight its dual protective and pathogenic functions, and discuss therapeutic strategies and future directions for targeting ISG15-related pathways in CNS diseases.