Ahelee Ghosal

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting 5–20% of reproductive-age women. Besides genetic factors, environmental triggers are considered major underlying causes that play a role through epigenetic alterations. Since epigenetic studies can be a possible link to explain the complexity of multifactorial disorders, it is worthwhile to investigate differentially methylated regions (DMRs) associated with PCOS. Therefore, a systematic review was conducted to identify epigenetic modifications associated with PCOS and analyse their functional role in the pathogenesis of the syndrome. After following inclusion and exclusion criteria, various databases (PubMed, Google Scholar, Central Cochrane Library, and Science Direct) were searched with predetermined keywords up to 30th June 2025, and quality of the selected articles assessed through the Newcastle Ottawa scale (NOS). In-silico analysis was performed by STRING, and Shiny GO. A total of 46 eligible studies were included, were further sub-categorized based on the sample type. A total of one hundred eleven genes were identified with altered DMRs, out of which thirty seven genes were reported from the ovarian tissues alone. Their GO analysis shows a significant interaction with other PCOS-susceptible genes and their functions in female sex differentiation and gonadal development. However, in-silico analysis of thirty six genes identified in blood showed their functions were significantly involved in the insulin-like growth factor binding activity. Gene enrichment analysis of fifteen genes with altered methylation identified in adipose tissue shows the significant involvement of female sex differentiation and insulin-activated receptor functions. Further, alterations in methylation of which genes (INSR, AMHR2, YAP1, CYP19A1, LHCGR, CDKN1A, LINE-1, AMH and TOX3) have been reported by at least two separate studies, irrespective of sample type. Their in-silico analysis shows significant involvement of these genes in the female sex characters, and gonadal development The current study highlights tissue-specific epigenetic modifications in PCOS, summarizes DMRs of genes which are involved in reproductive and insulin-related pathways. DMRs of identified genes may have a role in the pathogenesis of PCOS, insight into which may provide novel therapeutic targets in the future.