Mechanistic insights into cholesterol–bile acid metabolic dysregulation in ovarian aging

The convergence of delayed childbearing and modern lifestyle transitions has coincided with a global rise in female infertility and ovarian reserve disorders, positioning ovarian aging as a growing biomedical and public health concern. Accumulating evidence suggests that ovarian aging is not merely a time-dependent biological process but is increasingly shaped and accelerated by systemic metabolic stressors, including obesity, insulin resistance, and dyslipidemia. In contemporary reproductive-age populations, lipid metabolic abnormalities are disproportionately prevalent among infertile women and are closely associated with diminished ovarian reserve (DOR), menstrual irregularities, and adverse reproductive outcomes. Nevertheless, the mechanistic pathways through which systemic lipid overload is transduced into ovarian dysfunction remain incompletely elucidated.In this review, we advance a unified metabolic framework in which disruption of systemic cholesterol and bile acid homeostasis represents a central upstream driver of ovarian functional decline under pathological metabolic conditions. The ovary relies predominantly on peripheral lipoprotein-derived cholesterol to meet the demands of cyclic steroidogenesis and has limited capacity for cholesterol elimination or bile acid synthesis, features that render it susceptible to systemic metabolic disturbances. Efficient steroid hormone production requires coordinated sterol sensing, intracellular trafficking, and mitochondrial utilization, whereas disruption of this coordination impairs steroidogenic function.Obesity and chronic high-fat diet (HFD) exposure disrupt systemic lipid handling, such that lipid availability can exceed adipose storage capacity and hepatic processing, thereby driving the spillover of cholesterol and fatty acids into non-adipose tissues. Ectopic ovarian lipid deposition promotes lipotoxic stress, characterized by the accumulation of cytotoxic free cholesterol and free fatty acids, impaired mitochondrial fatty acid oxidation, increased reactive oxygen species, and activation of endoplasmic reticulum stress pathways. These insults suppress key steroidogenic checkpoints, particularly pathways governing mitochondrial cholesterol import, restricting steroid output. Consistent with this cellular phenotype, HFD is associated with depletion of primordial follicles, increased follicular atresia, macrophage infiltration, and chronic inflammatory activation, collectively accelerating ovarian reserve decline. In parallel, obesity remodels the circulating bile acid (BA) pool through coordinated changes in hepatic enzymatic activity and gut microbiota structure. Because the ovary expresses FXR and TGR5 but does not synthesize BAs, attenuation of FXR/TGR5 signaling plausibly weakens BA-dependent anti-inflammatory and mitochondrial protective programs, amplifying microenvironmental instability under metabolic stress. Finally, hypercholesterolemia-associated accumulation of oxysterols, particularly 27-hydroxycholesterol (27-HC), may further compromise granulosa cell function by acting as an LXR agonist and an endogenous ER antagonist, thereby perturbing differentiation programs and limiting aromatase expression when present above physiological ranges.We integrate clinical and translational evidence supporting the relevance of this axis in reproductive pathology. In patients with polycystic ovary syndrome (PCOS), dyslipidemia and bile acid alterations are associated with steroidogenic pathway reprogramming, insulin resistance, and hyperandrogenism, independent of body mass index. In DOR, follicular fluid metabolomic and transcriptomic profiles consistently reveal lipid overload, reduced secondary BAs, and coordinated downregulation of cholesterol transport and utilization pathways, indicating early attenuation of bile acid-dependent ovarian protective signaling. We further discuss emerging data suggesting that maternal lipid imbalance may exert transgenerational effects by shaping fetal sterol exposure and predisposing offspring ovaries to epigenetic vulnerability.Finally, we propose that therapeutic strategies targeting the cholesterol-bile acid-gut microbiota axis may offer a novel avenue for delaying ovarian aging. Interventions aimed at reducing systemic lipid burden, restoring bile acid composition, and reconstituting gut microbial function may provide a metabolism-informed approach to preserving ovarian function and extending female reproductive lifespan.