Deconstructing the RAGE signaling maze: the molecular key to opening a new dimension of ovarian anti-aging

Abstract The ovaries are vital components of the female reproductive system. Ovarian aging, driven by oxidative stress, chronic inflammation and hormonal dysregulation, severely compromises female fertility. The receptor for advanced glycation end products (RAGE) serves as a critical regulator of ovarian physiology and pathology. linking metabolic dysfunction to reproductive decline. This Review synthesizes evidence that RAGE hyperactivation, during the process of ovarian aging, disrupts folliculogenesis, granulosa cell function and steroidogenesis via MAPK-ERK, PI3K-AKT-mTOR and NF-κB pathways, exacerbating conditions such as premature ovarian failure, polycystic ovary syndrome and ovarian cancer. Furthermore, we summarizes existing therapeutic strategies targeting RAGE and underscores their potential in mitigating ovarian aging and treating ovarian pathologies, providing novel perspectives for preserving female reproductive capacity. We highlight therapeutic strategies targeting RAGE, including small-molecule inhibitors (Azeliragon and FPS-ZM1), soluble RAGE decoys and natural compounds, which show promise in restoring ovarian reserve and hormonal balance in preclinical models. These interventions mitigate advanced glycation end products (AGE)–RAGE-induced damage, offering novel avenues to preserve fertility. Beyond reproductive health, RAGE’s role in aging and metabolic disorders underscores its potential as a cross-disciplinary biomarker and therapeutic target. By bridging molecular mechanisms with clinical applications, this work provides a framework for developing precision therapies to combat ovarian aging, with implications for endocrinology, oncology and geroscience.