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

www.nature.com/emm REVIEW ARTICLE OPEN Deconstructing the RAGE signaling maze: the molecular key to opening a new dimension of ovarian anti-aging Xia Bai1,3, Guohui Zhang2,3, Xiao Xiao1, Qin Zeng2, Yuhong Zhao1, Pinghan Wang1, Fangyi Long1 ✉ and Weixin Liu2 ✉ © The Author(s) 2026 1234567890();,: 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. Experimental & Molecular Medicine (2026) 58:1063–1085; https://doi.org/10.1038/s12276-026-01678-3 FACTS ● ● ● ● RAGE-induced oxidative stress reduces follicular quality in aging ovary. RAGE induces granulosa cell dysfunction: autophagic disruption and hormonal dysregulation. RAGE causes fibrosis of the ovarian stroma, integrating changes in the ovarian microenvironment. RAGE inhibitors hold promise for treating age-related ovarian decline. OPEN QUESTIONS ● ● ● What is the core mechanism of RAGE overexpression leading to ovarian aging? Can tissue-specific RAGE inhibition strategies overcome the limitations of systemic RAGE antagonists to effectively delay ovarian aging while preserving physiological RAGE functions in other organs? Why does RAGE overexpression manifest as divergent pathologies and do ligand-specific interactions or genetic variants dictate these distinct clinical phenotypes? INTRODUCTION The global demographic transition has been marked by a precipitous decline in fertility rates, synergistically driving accelerated population aging that presents unprecedented challenges to global socioeconomic sustainability1. This fertility recession arises from a complex interplay of sociobehavioral and biological determinants, where declining reproductive autonomy intersects with an age-related decline in the ovarian reserve. From a biological perspective, maternal aging is intrinsically linked to progressive ovarian functional decay characterized by diminished follicular quantity/quality and altered endocrine dynamics, establishing a finite window of reproductive competence. Ovaries regulate female reproduction through gametogenic/ steroidogenic functions2. Cyclical oocyte maturation requires coordinated nuclear/cytoplasmic development, determining reproductive success. Postovulatory transport facilitates spermoocyte fusion and embryogenesis via blastocyst development/implantation3,4. The ovarian endocrine axis secretes dynamic hormones (estradiol, progesterone and inhibins) under hypothalamic–pituitary–ovarian (HPO) axis regulation, involving multilevel feedback5. Pulsatile gonadotropin-releasing hormone (GnRH) stimulates pituitary follicle-stimulating hormone (FSH)/luteinizing hormone (LH) production6, with FSH driving follicular maturation and LH surge inducing 1 Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital/The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, China. Center for Reproductive Medicine, Sichuan Provincial Women’s and Children’s Hospital/The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, Chengdu, China. 3These authors contributed equally: Xia Bai, Guohui Zhang. ✉email: ; 2 Received: 7 July 2025 Revised: 26 December 2025 Accepted: 28 December 2025 Published online: 20 April 2026 X. Bai et al. 1064 Fig. 1 Schematic diagram of HPO axis. The HPO axis uses pulsatile GnRH to control pituitary LH/FSH release, which bind ovarian receptors (LHR/FSHR) to trigger folliculogenesis and steroid production. Sex hormones feedback to suppress GnRH/gonadotropins, while estrogen briefly boosts GnRH mid-cycle. Inhibin also selectively lowers FSH, synchronizing hormone cycles. Image created with BioRender; https:// www.biorender.com/. ovulation/corpus luteum formation7. Steroid hormones modulate GnRH/gonadotropin secretion via feedback loops8. Molecular studies reveal HPO regulation through kisspeptinergic pathways, AMH dynamics and growth factor interactions9 (Fig. 1). Notably, the pathophysiology of age-related ovarian senescence manifests through multifactorial desynchronization of gonadotropic feedback mechanisms, encompassing both quantitative depletion of primordial follicle reserves and qualitative alterations in gonadotropin receptor responsiveness—representing fundamental pathophysiological mechanisms underlying the progressive decline in fecundity observed in advanced reproductive aging10. The physiological process of ovarian aging is characterized by progressive depletion of the primordial follicle reserve, concomitant with reactive oxygen species (ROS)-mediated oxidative stress that induces mitochondrial DNA (mtDNA) damage11,12. This dual mechanism ultimately culminates in oocyte apoptosis and functional impairment of granulosa cells. Simultaneously, the aging ovarian microenvironment sustains a persistent low-grade inflammatory milieu, evidenced by elevated proinflammatory cytokine production that drives stromal fibrosis and microvascular degeneration13–15. At the molecular level, granulosa cells exhibit downregulation of steroidogenic enzymes such as aromatase and 3β-hydroxysteroid dehydrogenase, precipitating diminished estrogen and progesterone synthesis that underlies menopausal symptomatology16. Notably, ovarian pathophysiological conditions have emerged as critical determinants of global fertility decline. Polycystic ovary syndrome (PCOS), with a worldwide prevalence of 6-20%, induces anovulatory i (...truncated)