Comprehensive Signaling Network Dysregulation in Polycystic Ovary Syndrome: Integrating Genetic, Epigenetic, and Metabolic Pathways Toward Precision Medicine

Abstract

Polycystic Ovary Syndrome (PCOS) is one of the metabolic disorders affecting females of reproductive age, with a complex, multifactorial etiology. This review aims to consolidate the current understanding of PCOS, delving into its heterogeneous pathophysiology, which is characterized by the interplay of genetic, epigenetic, environmental, and gut microbiome factors. We explore the core pathogenic pathways, including insulin resistance (IR) and hyperinsulinemia, hyperandrogenism, neuroendocrine dysfunction, and chronic low-grade inflammation. Numerous intricate signaling pathways, such as The PI3K/Akt/mTOR,  MAPK/ERK, AMPK, TGF-β, Superfamily Wnt β-Catenin,  Hh , Notch, JAK-STAT, NF-κB, JNK, p38 MAPK, TLR4, Inflammasome, SIRT1, FOXO1, PPARγ, LKB1/AMPK, LKB1, LKB1/AMPK, LKB1, mTORC1, cAMP/PKA, Autophagy, Autophagy, Endocannabinoid System and Kisspeptin/KISS1R are involved in these events. Furthermore, the review examines the role of epigenetics, specifically DNA methylation and miRNA dysregulation, in mediating the disease phenotype. We compiled clinically significant genes like the DENND1A, FSHR, LHCGR, INSR as well as THADA. and discuss their interactions. The proliferating field of gut dysbiosis and its bidirectional relationship with PCOS pathogenesis is also highlighted. Finally, we summarize current and emerging therapeutic strategies, from conventional insulin sensitizers and lifestyle modifications to novel targets informed by genetic and pathway analyses, concluding with future perspectives on personalized medicine for PCOS management.