Postnatal ketone deficiency impairs adult oocyte quality via enhancing histone acetylation in malnourished mice.

Early postnatal life is important for reproductive development, but the effects of early-life nutrition on female reproductive capacity remain largely unknown. Here, we investigated whether neonatal ketone body deficiency affects adult oocyte quality using a lactational malnutrition model and Hmgcs2-deficient mice. We found that impaired neonatal ketogenesis caused long-lasting impairments in female reproductive function, including reduced ovarian reserve, decreased oocyte developmental competence, altered hormone levels, and impaired embryo development. Neonatal β-hydroxybutyrate (β-HB) supplementation partially improved these reproductive abnormalities, indicating an important role of ketone metabolism during early ovarian development. Transcriptomic and epigenomic analyses showed that Hmgcs2 deficiency disrupted histone H3 acetylation homeostasis in oocytes. These Ace-H3 changes were enriched in genes related to oxidative stress and apoptosis and were accompanied by transcriptional alterations. β-HB supplementation partially restored the altered Ace-H3 patterns. Together, our findings reveal that ketone bodies regulate oocyte development by connecting early-life nutrition with epigenetic regulation.