NR4A1 ‐Driven Granulosa Cell Ferroptosis Contributes to Obesity‐Related Ovarian Dysfunction and Metformin‐Mediated Ovarian Protection

ABSTRACT Obesity triggers ovarian dysfunction and female infertility accompanied by granulosa cell damage. Ferroptosis, iron‐dependent lipid peroxidation‐mediated cell death, participates in multiple reproductive diseases, yet the molecular cascade linking metabolic obesity to granulosa ferroptosis remains undefined. Using high‐fat diet obese mice, primary human granulosa cells from obese infertile patients, and KGN cell lines, we identified the nuclear receptor NR4A1 as a key mediator of obesity‐induced ferroptosis downstream of PI3K/AKT signaling. Elevated NR4A1 was associated with upregulated ACSL4 and suppressed GPX4, accompanied by iron overload, lipid peroxidation, and mitochondrial collapse, impairing folliculogenesis and oocyte quality. Metformin reduced NR4A1 activation in association with PI3K/AKT signaling modulation, thereby attenuating ferroptotic injury and contributing to the restoration of ovarian function. In vivo NR4A1 agonist administration attenuated the protective effects of metformin, while ovarian‐specific NR4A1 knockdown alleviated HFD‐triggered ovarian ferroptosis. Single‐cell RNA‐seq further suggested that metformin remodels oocyte redox and folliculogenic transcriptional networks. These findings support a role for the PI3K/AKT–NR4A1 signaling pathway in driving ferroptosis during obesity‐related ovarian dysfunction and suggest a potential anti‐ferroptotic mechanism of metformin in this context.