Genetic and Epigenetic Basis of Polycystic Ovary Syndrome:A Systematic Review

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder characterized by complex interactions among genetic, epigenetic, metabolic and endocrine factors. This review aimed to provide an integrated overview of the molecular mechanisms underlying PCOS, with particular emphasis on their potential relevance to disease heterogeneity, diagnosis, and targeted therapy.

A comprehensive literature search was conducted in PubMed and Google Scholar to identify English-language studies published up to February 2025. Keywords and Medical Subject Headings (MeSH) related to PCOS, genetics, epigenetics, non-coding RNAs, metabolism, insulin resistance, signaling pathways, and autophagy were combined using the Boolean operators "AND" and "OR". Eligible original, review, experimental, and clinical studies were screened, and relevant data on molecular mechanisms, biomarkers, and signaling pathways were extracted and synthesized narratively.

Current evidence indicates that PCOS pathogenesis involves interconnected alterations in genetic susceptibility, epigenetic regulation, mitochondrial function, metabolic signaling and endocrine homeostasis. Noncoding RNAs, including miRNAs and lncRNAs, as well as DNA methylation, appear to contribute to the regulation of these processes. Emerging findings also suggest a potential role for PGK1 in linking metabolic reprogramming, androgen signaling and ovarian dysfunction. Collectively, these molecular mechanisms may contribute to PCOS heterogeneity and provide potential biomarkers and therapeutic targets.

PCOS should be considered a complex molecular disorder arising from interactions among genetic, epigenetic, metabolic, mitochondrial and endocrine mechanisms rather than from isolated pathogenic pathways. Integrating these mechanisms may improve understanding of disease heterogeneity and support development of more accurate biomarkers and personalized therapeutic strategies. However, clinical relevance of the emerging targets, such as PGK1 and mitochondrial regulatory pathways, requires further validation.