Ferroptosis and ovarian senescence: integrating lipid metabolism, iron homeostasis, and established aging pathways

Female reproductive aging is a major determinant of declining fertility and is characterized by progressive depletion of the follicular reserve together with deterioration in oocyte quality. Established contributors include mitochondrial dysfunction, oxidative stress, genomic instability, chronic inflammation, and altered intercellular communication within the ovarian niche. However, these mechanisms do not fully explain the marked heterogeneity in ovarian aging trajectories or the limited efficacy of current interventions. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation and failure of antioxidant defenses, has recently emerged as a candidate pathway relevant to age-associated tissue degeneration. In this review, we critically evaluate current evidence linking ferroptosis to ovarian aging and related reproductive disorders. We examine how age-associated alterations in iron handling, lipid remodeling, glutathione metabolism, GPX4 activity, mitochondrial stress, and inflammatory signaling may increase ferroptotic susceptibility in ovarian somatic cells and oocytes. We further compare this framework with established mechanisms of ovarian aging, including apoptosis, autophagy dysfunction, DNA damage responses, and metabolic decline, to position ferroptosis within a broader hallmarks-of-aging context. Available evidence from rodent models, cellular systems, and emerging human transcriptomic or follicular-fluid studies suggests that ferroptosis-related pathways may contribute to follicular attrition, granulosa-cell dysfunction, impaired oocyte competence, and accelerated ovarian decline under conditions such as chemotherapy exposure, endometriosis, and metabolic disease. Nonetheless, direct causal evidence in humans remains limited, and most mechanistic data derive from preclinical models. We propose that ferroptosis should currently be viewed not as a singular driver of ovarian senescence, but as a potentially important interacting mechanism that converges with other aging pathways. Finally, we discuss translational opportunities and limitations, including biomarker development, omics-based ferroptosis signatures, targeted antioxidant or iron-modulating strategies, and priorities for future ovary-specific in vivo and human studies.