Mechanism and Intervention of the <scp>NPY1R</scp> / <scp>CREB</scp> Signaling Axis in Regulating Inflammatory Response in Aged Ovarian Granulosa Cells and Ovarian Senescence

ABSTRACT Ovarian senescence is accompanied by inflammatory responses, yet the underlying mechanism remains incompletely elucidated. In this study, transcriptome sequencing was performed on ovarian granulosa cells from advanced‐age patients and normal (Ctrl) patients, revealing that Neuropeptide Y Y1 Receptor (NPY1R) was significantly upregulated in aged granulosa cells. In vivo experiments confirmed that the NPY1R agonist [Leu 31 , Pro 34 ]‐NPY induced estrous cycle disorder, inhibited follicular development, triggered reactive oxygen species (ROS) accumulation and mitochondrial structural damage in oocytes, thereby inducing ferroptosis, and ultimately leading to ovarian dysfunction and compromised oocyte quality; conversely, the NPY1R antagonist BIBO 3304 effectively reversed these phenotypes. Mechanistic studies demonstrated that NPY1R overexpression activates the p‐CREB signaling pathway, promotes the expression of pro‐inflammatory factor IL‐6 and inflammasome NLRP3, aggravates ferroptosis, mitochondrial dysfunction, and type I/III collagen imbalance, and ultimately accelerates ovarian aging. Collectively, this study clarifies that the NPY1R/CREB signaling axis participates in ovarian senescence by regulating inflammatory responses, and reveals its pivotal role in follicular development and oxidative stress. Targeting NPY1R is expected to be a potential therapeutic strategy for improving ovarian function and infertility in advanced‐age women.