Hypomethylation‐Triggered SERPINE1 (Serpin Family E Member 1) Exacerbates Polycystic Ovary Syndrome with Hyperandrogenism Induced by Circadian Disruption

Polycystic ovary syndrome (PCOS), a prevalent cause of female infertility, arises from complex interactions between genetic and environmental factors, with hyperandrogenism serving as a core pathological feature. 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-week 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-dCas9-based targeted methylation, we found that CpG hypomethylation near the SERPINE1 transcription start site drove its overexpression. Functional assays revealed that SERPINE1 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-induced hyperandrogenism and its potential as a methylome-based diagnostic biomarker for PCOS. Pharmacological inhibition of SERPINE1 emerges as a promising therapeutic strategy for hyperandrogenic PCOS.