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While growing evidence links circadian disruptions to the development of hyperandrogenism in PCOS, the underlying mechanism remains unclear. In this study, we employed DNA methylation profiling and RNA sequencing of ovarian granulosa cells from rats exposed to 8\u2010week darkness, and identified serpin family E member 1 (SERPINE1) as a key player. SERPINE1 was significantly hypomethylated and upregulated in the dark group, correlating with elevated androgen levels. Mechanistically, using CRISPR\u2013dCas9\u2010based targeted methylation, we found that CpG hypomethylation near the SERPINE1 transcription start site drove its overexpression. Functional assays revealed that\u00a0SERPINE1 suppression activated the PI3K\/AKT signaling pathway, thereby enhancing CYP19A1 expression and enzymatic activity to facilitate androgen conversion in vitro. Moreover, treatment with the SERPINE1 inhibitor tiplaxtinin alleviated both reproductive and metabolic abnormalities in rat models treated with either dehydroepiandrosterone or exposed to darkness. These findings highlight SERPINE1's role in circadian disruption\u2010induced hyperandrogenism and its potential as a methylome\u2010based diagnostic biomarker for PCOS. Pharmacological inhibition of SERPINE1 emerges as a promising therapeutic strategy for hyperandrogenic PCOS.<\/jats:p>","DOI":"10.1002\/mco2.70270","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T03:24:04Z","timestamp":1751599444000},"source":"Crossref","is-referenced-by-count":2,"title":["Hypomethylation\u2010Triggered SERPINE1 (Serpin Family E Member 1) Exacerbates Polycystic Ovary Syndrome with Hyperandrogenism Induced by Circadian\u00a0Disruption"],"prefix":"10.1002","volume":"6","author":[{"given":"Xueying","family":"Geng","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine Ren Ji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Reproductive 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