Ergostane Steroid-Rich Cranberry Exosomes Restore Ovarian Function in High-fat and high-sugar diet Diet-Induced Premature Ovarian Failure

Abstract Cranberry-derived exosome-like nanovesicles (Va-exo) are evaluated for their therapeutic potential in high-fat and high-sugar diet–induced premature ovarian failure (HFHS-POF) in mice. Va-exo displays typical exosomal morphology, size distribution, and zeta potential, and contains abundant plant metabolites, including fatty acids, carbohydrates, and ergostane steroids. Oral administration of Va-exo significantly improves ovarian morphology, increases ovarian weight, reduces atretic follicles, and restores anti-Müllerian hormone (AMH) and estradiol (E2) levels while lowering follicle-stimulating hormone (FSH). Va-exo reduces granulosa cell senescence, enhances proliferation, improves mitochondrial function, and regulates lipid metabolism. Metabolomic analysis reveals ergostane steroids, particularly campestanol, as key bioactive components shared between Va-exo and cranberry. Oral delivery of campestanol replicates Va-exo’s therapeutic effects, restoring granulosa cell morphology, reducing follicular atresia, normalizing sex hormone levels, and decreasing cellular senescence markers. These findings indicate that Va-exo exerts potent therapeutic effects in HFHS-POF by delivering ergostane steroids, offering a safe, plant-derived, nanovesicle-based strategy for restoring ovarian function.