Epigenetic Regulation of Ferroptosis in Polycystic Ovary Syndrome: Emerging Molecular Insights

Polycystic ovary syndrome (PCOS) is a complex endocrine–metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, insulin resistance, and chronic low-grade inflammation. Although genetic predisposition contributes to disease susceptibility, accumulating evidence suggests that epigenetic modifications play a critical role in modulating gene expression in PCOS without altering the underlying DNA sequence. DNA methylation, histone modifications, and microRNA dysregulation have been implicated in abnormal steroidogenesis, impaired insulin signaling, and disrupted folliculogenesis. Concurrently, ferroptosis—an iron-dependent, lipid peroxidation-driven form of regulated cell death—has emerged as a potential contributor to ovarian dysfunction. Increased oxidative stress, altered iron metabolism, and reduced antioxidant defense mechanisms observed in PCOS create a cellular environment conducive to ferroptotic damage, particularly within granulosa cells essential for follicular maturation.

Recent studies suggest that epigenetic alterations may influence the expression of key ferroptosis-regulating genes, including GPX4, SLC7A11, and iron-handling proteins, thereby enhancing cellular susceptibility to oxidative injury. This integrated perspective proposes that epigenetic dysregulation may serve as an upstream mechanism that sensitizes ovarian tissue to ferroptosis, linking metabolic stress and reproductive dysfunction in PCOS. Understanding this epigenetic–ferroptotic interplay may provide novel insights into disease pathogenesis and identify potential biomarkers and therapeutic targets. This review synthesizes current evidence on epigenetic mechanisms and ferroptotic signaling in PCOS and highlights future research directions to clarify their mechanistic crosstalk.

Polycystic Ovary Syndrome, Epigenetics, Ferroptosis, Oxidative Stress, Granulosa Cells

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