Senescent repair memory in chronic disease: Failed resolution as a driver of persistent organ dysfunction.

Chronic diseases can continue to progress after the initiating insult has subsided, indicating that injured tissues may retain a persistent imprint of failed repair. Here, senescent repair memory refers to a tissue state in which transient repair-associated senescence fails to resolve and is maintained by persistent senescent cells, altered secretory and metabolic programmes, defective immune clearance, epigenetic stabilization and spatial niche interactions. Once established beyond the adaptive repair window, this state can perpetuate inflammation, fibrosis and functional decline even after the original injury has diminished. This Review examines how failed resolution may contribute to chronic kidney disease, cardiovascular disease, pulmonary fibrosis, metabolic liver disease, neurodegeneration and osteoarthritis. Evidence is strongest in kidney disease, pulmonary fibrosis and metabolic liver disease. Cardiovascular disease and osteoarthritis are supported mainly by experimental or associative studies, whereas the application of this model to neurodegeneration remains largely indirect. Senescent repair memory is therefore presented not as a new molecular pathway or a universal explanation for chronic disease, but as a testable framework linking the persistence, maintenance, spatial organization and functional consequences of unresolved senescence. By distinguishing adaptive repair from disease-sustaining senescence, this perspective may inform the development of stage- and tissue-specific biomarkers and interventions.