Abstract

Reduced fertility has become a global health problem. Female fertility is closely related to the normal physiological function of the ovary. Stress has been implicated in ovarian dysfunction, but the mechanisms driving this association are poorly understood. Norepinephrine (NE), a classic stress hormone, has not been extensively studied in the context of ovarian function. This study aimed to investigate the molecular mechanism of NE-induced ferroptosis in ovarian granulosa cells. Our results demonstrate that NE activates the adrenergic α1receptor, resulting in elevated intracellular calcium levels and subsequent downregulation of FDXR gene expression. This disruption in FDXR expression dysregulates iron metabolism in the ovary, leading to iron accumulation, increased reactive oxygen species (ROS), and lipid peroxidation. These changes are accompanied by elevated levels of lipid peroxidation products, including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Ultimately, these processes induce mitochondrial damage, trigger ferroptosis in granulosa cells, and lead to ovarian dysfunction. These findings reveal a stress-induced pathway driving ovarian decline, suggesting α1 antagonists or FDXR modulation as therapeutic strategies.