The Mechanism of Ferroptosis Regulating Granulosa Cell Apoptosis and Oxidative Stress Through the NF-κB/PTGS2 Axis in Porcine Atretic Follicles

Ferroptosis is a new mode of cell death, which is characterized by inducing the accumulation of lipid peroxides dependent on iron ions and reactive oxygen species. It has been found that ferroptosis can lead to follicle atresia by promoting granulosa cell death and increasing its reactive oxygen species content, but the specific mechanism has not been elucidated. Through transcriptome sequencing, we found that ferroptosis markers and related genes were upregulated in porcine atretic follicles. PTGS2 was found to be differentially expressed between atretic and healthy follicles. By inhibiting NF-κB nuclear translocation, inhibition of the PTGS2 gene expression reduced the degree of ferroptosis in granulosa cells and rescued granulosa cell death and oxidative stress caused by ferroptosis. Therefore, we propose that the NF-κB/PTGS2 axis plays a key role in ferroptosis-induced granulosa cell death, leading to follicular atresia. Melatonin, a neurohormone secreted by the pineal gland of the upper thalamus, is involved in the regulation of various metabolic, immune, reproductive, and other processes. In the ferroptosis treatment group, melatonin treatment alleviated the degree of ferroptosis (downregulation of ferroptosis marker genes and markers) and decreased the expression of PTGS2. In summary, we have demonstrated that melatonin inhibits ferroptosis via the NF-κB/PTGS2 axis in granulosa cells.