Aging Dis. 2026 Jan 5. doi: 10.14336/AD.2025.1258. Online ahead of print.
ABSTRACT
The prevalence of aging-related diseases, including tumors, cardiovascular and cerebrovascular diseases, and fibrotic diseases, has been consistently increasing in the aging population. In these conditions, nucleolar stress response mechanisms, such as defective ribosome biogenesis and dysregulated DNA damage repair, play instrumental roles in disease initiation and progression. Nucleophosmin 1 (NPM1), a multifunctional nucleolar chaperone, helps maintain cellular homeostasis through these stress response pathways. Accumulating evidence reveals that NPM1 exhibits disease-type-specific, and sometimes dual, roles in tumorigenesis, vascular aging, and multi-organ fibrosis, positioning it as a central regulator of age-related pathological processes. This review summarizes the role of NPM1 in the pathogenesis and treatment of multi-system aging-related diseases. We explore NPM1-related signaling pathways that regulate nucleolar stress responses and cellular homeostasis, evaluate its potential as a predictive biomarker for aging-related diseases, and discuss therapeutic strategies targeting NPM1-associated signaling. Although growing evidence highlights the potential of NPM1 inhibitors to modulate signaling cascades and improve clinical outcomes, context-selective inhibition of NPM1 may unexpectedly worsen disease progression in certain settings, underscoring its functionally dual nature depending on the context of the disease. This review delineates NPM1 signaling as a central orchestrator in aging-related pathogenesis and supports its potential as a therapeutic target to enhance treatment efficacy.
PMID:41525177 | DOI:10.14336/AD.2025.1258