摘要：SummaryCellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cellsin vivoby targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture andin vivoin mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.Graphical abstractDisplay OmittedHighlights•Single cell sequencing can be used to facilitate discovery of senolytic targets•CRYAB is a senolytic target in multiple human and mouse cell types•25-hydroxycholesterol is a naturally produced senolytic•25-hydroxycholesterol senolysis was validated in mice using the biomarker 15-dPGJ2Biological sciences; Molecular biology; Cell biology; Transcriptomics
