Integrated cellular and molecular mechanisms of neuropsychiatric dysfunction in polycystic ovary syndrome

Neuropsychiatric conditions such as depression, anxiety, and stress-related disorders are increasingly associated with Polycystic Ovary Syndrome (PCOS). Evidence suggests that these conditions are not only linked to the metabolic features of PCOS but also share common underlying mechanisms, including hormonal imbalance, neuroendocrine dysfunction, chronic inflammation, and epigenetic changes. Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) regulation, may act as important links between endocrine abnormalities and changes in brain function. In this review, we summarize current evidence connecting PCOS with psychiatric disorders through disruptions in the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes, neurotransmitter imbalance, and metabolic dysregulation. Altered activity of DNA methyltransferases and locus-specific methylation changes in stress-responsive genes, including FKBP5, have been associated with dysregulated HPA function. Similarly, histone-modifying enzymes such as histone deacetylases (HDAC1/2) and enhancer of zeste homolog 2 contribute to transcriptional changes in genes involved in synaptic plasticity and neuroendocrine regulation under conditions of hyperandrogenism and insulin resistance. In addition, epitranscriptomic regulation via N⁶-methyladenosine (m6A) modification, mediated in part by fat mass and obesity-associated protein (FTO), influences neuronal activity of gonadotropin-releasing hormone and neurotransmitter signaling. Dysregulated ncRNAs, including microRNAs (miR-34a, miR-155, miR-93, and miR-221) and long ncRNAs (XIST, H19, and MALAT1), further connect inflammatory and metabolic disturbances with neuronal function. Therefore, this review links PCOS to psychiatric disorders through alterations in the HPG and HPA axes, neurotransmitter imbalance, metabolic dysfunction, and epigenetic reprogramming. We further propose an integrated neuroendocrine-epigenetic framework to explain psychiatric vulnerability in PCOS and discuss future directions for precision-targeted therapeutic strategies.