Epigenetic Targeting of Senescent Cells Prevents the Deleterious Effects of Obstructive Sleep Apnea on Growing Skeleton

Abstract Obstructive Sleep Apnea Syndrome (OSAS) is a common sleep disorder characterized by chronic intermittent hypoxia (CIH), which has been increasingly recognized for its systemic effects on pediatric skeletal development. However, the mechanism by which CIH influences bone growth and homeostasis remains largely unexplored. In this study, it is demonstrated that CIH exposure in young murine models induces cellular senescence within the metaphysis of long bones, resulting in compromised bone formation and growth retardation. Through single cell sequencing and in situ immunostaining, it is identified that the senescent cells predominantly consist of osteoprogenitors. Mechanistically, CIH enhances the activity of hypoxia‐inducible factor 1‐alpha (HIF‐1α) in osteoprogenitors and subsequently downregulates trimethylation of histone H3 at lysine 27 (H3k27me3) through the suppression of polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2), thereby facilitating the expression of senescence‐associated genes. Employing both genetic and pharmacological strategies, it is demonstrated that the restoration of H3K27me3 levels via UTX inhibition (achieved through in vivo knockout or GSK‐J4 treatment) effectively prevents CIH‐induced senescence, promotes osteogenesis, and alleviates bone loss and growth retardation. These findings elucidate a novel epigenetic mechanism that underlies the skeletal impairments associated with CIH and underscore the therapeutic potential of targeting histone methylation to mitigate hypoxia‐induced bone defects.