Ginsenoside Rb1 alleviates uterine aging via AMPK-mediated mTOR inactivation

Uterine aging impairs fertility and reproductive health, but the underlying pathogenic mechanisms and effective treatment strategies remain elusive. Defective endometrial decidualization and implantation failure are hallmarks of uterine aging, which can be driven by cellular senescence, especially in endometrial stromal cells (EnSCs). Rb1 has been reported to relieve cellular senescence by suppressing oxidative and inflammatory pathways. However, whether Rb1 functions in alleviating uterine aging remains uncertain. Here, we demonstrate that Rb1 can attenuate oxidative stress, senescence, and apoptosis in the EnSCs of the aging human endometrium and murine uterus. Further proteomic analysis reveals that Rb1 safeguards against endometrial aging by regulating mammalian target of rapamycin (mTOR)-related pathways. Rb1 treatment results in the activation of AMP-activated protein kinase (AMPK) and AMPK-mediated suppression of the mTOR-nuclear factor-kappa B (NF-κB) signaling loop, thereby ameliorating aging-related phenotypes. Collectively, our findings illustrate that Rb1 alleviates uterine aging by attenuating endometrial stromal cell senescence and suppressing AMPK-mTOR-NF-κB-driven inflammatory signaling. Rather than selectively eliminating senescent cells, Rb1 primarily targets senescence-associated dysfunction and restores endometrial homeostasis, highlighting its potential as a senescence-modulating therapeutic strategy for uterine aging.