The ISG15 Axis: A Central Mediator and Therapeutic Target in Vascular Inflammaging

Vascular aging, which is characterized by the progressive decline in the structure and function of blood vessels, is a primary driver of cardiovascular morbidity and mortality in older adults. Although chronic low-grade inflammation (inflammaging) and cellular senescence are central to this process, the molecular nodes that integrate these pathways are not well understood. This review proposes that interferon-stimulated gene 15 (ISG15), a well-established ubiquitin-like modifier in antiviral defense, acts as a critical nexus linking these pathological hallmarks in vascular aging. ISG15 is proposed to function through a dual mechanism: extracellularly, it propagates pro-inflammatory signaling; intracellularly, its covalent conjugation to target proteins (ISGylation) disrupts core homeostatic processes. The review presents evidence demonstrating that the ISG15 system, when activated by sterile triggers via the cGAS-STING pathway, drives endothelial dysfunction and vascular smooth muscle cell phenotypic switching by exacerbating oxidative stress, inducing cellular senescence, and disrupting proteostasis. Consequently, the ISG15 axis is established as a compelling therapeutic target. The rationale behind strategies that range from the direct inhibition of ISGylation and the neutralization of extracellular ISG15, to the repurposing of existing upstream interferon-pathway inhibitors, is discussed. Key outstanding questions are outlined to guide future research, paving the way for novel diagnostics and interventions aimed at preserving vascular health during aging.