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This study investigates prenatal aspirin exposure (PAE) on ovarian reserve in female offspring. Pregnant mice received aspirin (5, 10, and 20 mg\/kg\u00b7d) from gestational days 918. Morphological and functional analyses of ovaries across prenatal to postnatal stages revealed PAE (20 mg\/kg\u00b7d) reduced primordial and antral follicle counts, increased follicular atresia, and impaired ovulation in adulthood. Transcriptomics identified sustained downregulation of\n                    <jats:italic>Usp9x<\/jats:italic>\n                    as a potential mediator, which correlated with suppression of the HIF1\u03b1\/NOBOX signaling axis. Mechanistically, our data suggest that aspirin exposure is associated with increased HDAC1 activity and enrichment of HDAC1 at the\n                    <jats:italic>Usp9x<\/jats:italic>\n                    promoter, accompanied by a reduction of H3K27ac marks, thereby potentially epigenetically silencing\n                    <jats:italic>Usp9x<\/jats:italic>\n                    expression. This enhanced HIF1\u03b1 ubiquitination and degradation, ultimately attenuating NOBOX\u2010mediated transcriptional regulation of downstream follicular genes. Using in vitro fetal ovarian cultures and NIH3T3 cells, we confirmed aspirin's disruption of primordial follicle assembly via the USP9X\u2010HIF1\u03b1\u2010NOBOX pathway. Crucially, HDAC1 knockdown or pharmacological inhibition rescued USP9X expression and restored follicular development. Our findings indicate that PAE reduces ovarian reserve through HDAC1\u2010linked epigenetic silencing of\n                    <jats:italic>Usp9x<\/jats:italic>\n                    , exacerbating HIF1\u03b1\/NOBOX pathway dysfunction, thereby informing aspirin's gestational safety and future interventions for fetal\u2010origin ovarian disorders.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507679","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T12:26:35Z","timestamp":1768220795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["USP9X as a Candidate Mediator of Prenatal Aspirin\u2010Induced Ovarian Reserve Reduction in Offspring Mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Yating","family":"Li","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology Zhongnan Hospital of Wuhan University  Wuhan China"},{"name":"Department of 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