Abstract
Oocyte quality is critical for fertilization and embryo development. Recent studies have shown that ferroptosis may compromise oocyte quality. Ferroptosis suppressor protein 1 (FSP1) is a ferroptosis inhibitor with an undefined role in oocyte quality regulation during meiotic maturation. Here, we found that FSP1 is expressed throughout all stages of meiotic maturation and localizes to the cytoplasm of mouse oocytes. A decline in FSP1 expression was observed in the ovaries and oocytes of aged mice. Pharmacological inhibition of FSP1 caused a failure in germinal vesicle breakdown and polar body emission, accompanied by spindle abnormalities and chromosome misalignment. Moreover, FSP1 inhibition consistently activated the spindle assembly checkpoint, inducing meiotic arrest. Mechanistically, FSP1 inhibition increased Fe2+ content, elevated dihydroethidium levels, promoted reactive oxygen species buildup, and heightened lipid peroxidation. Additionally, it dysregulated the expression of ferroptosis-related genes, suggesting that oocytes underwent ferroptosis. Furthermore, FSP1 inhibition provoked mitochondrial dysfunction, characterized by abnormal mitochondrial localization, reduced ATP levels, and elevated mitochondrial membrane potential. In summary, our findings demonstrate that FSP1 participates in oocyte meiotic maturation through its involvement in iron homeostasis and mitochondrial activity, and FSP1 inhibition results in ferroptosis-dependent meiotic failure.