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

Apr 9, 2026The journals of gerontology. Series A, Biological sciences and medical sciences

The ISG15 Pathway: A Key Driver and Treatment Target in Blood Vessel Aging and Inflammation

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Abstract

Interferon-stimulated gene 15 (ISG15) is proposed as a critical link between chronic inflammation and cellular aging in blood vessels.

Vascular aging is associated with a decline in blood vessel function and structure, contributing to cardiovascular issues in older adults.
Chronic low-grade inflammation and cellular senescence are central processes involved in vascular aging.
ISG15 may propagate inflammation and disrupt normal cellular processes through a mechanism that includes both extracellular signaling and intracellular modifications.
Activation of the ISG15 system can lead to endothelial dysfunction and changes in vascular smooth muscle cells by increasing oxidative stress and promoting cellular aging.
Strategies targeting ISG15, such as inhibiting its conjugation to proteins or neutralizing its extracellular effects, could offer therapeutic potential.

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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.

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

Abstract

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