Iron dysmetabolism in ovarian follicles: implications for oocyte quality and embryo development in endometriosis

RESEARCH QUESTION: Do iron metabolism and ferroptosis influence oocyte and embryo quality in patients with endometriosis undergoing IVF/intracytoplasmic sperm injection (ICSI), or in a mouse model? DESIGN: Fifty-seven patients with laparoscopically confirmed endometriosis and 153 age-matched controls (1:3 ratio) were included in this study. Embryological outcomes were assessed, and follicular fluid was analysed for iron and oxidative stress markers. Ferroptosis-related protein expression in granulosa cells was evaluated by Western blot. Mechanistic insights were explored using human KGN granulosa cells and mouse oocyte/embryo models under iron overload [100 μM ferroptosis activator (FAC)] with or without ferrostatin-1 (Fer-1; 2 μM). RESULTS: Patients with endometriosis showed impaired oocyte maturation and poorer embryo quality compared with controls. Follicular fluid of patients with endometriosis exhibited elevated Fe2+ (P = 0.0017), malondialdehyde (P < 0.001) and total superoxide dismutase (P < 0.001), indicating iron overload and oxidative stress. Granulosa cells displayed enhanced ferroptosis. In KGN cells, iron overload (100 μM FAC) reduced glutathione peroxidase 4 (P < 0.001), and increased peroxiredoxin 3 (P = 0.044) and reactive oxygen species; these effects were reversed by Fer-1. In mice, iron overload decreased oocyte maturation (P = 0.0429), increased abnormal spindle formation (P = 0.0034) and chromatin misalignment (P = 0.002), and reduced mitochondrial membrane potential (P < 0.001). Fer-1 treatment restored oocyte maturation (P = 0.0109), and improved spindle morphology (P = 0.0322), chromatin alignment (P = 0.0271) and mitochondrial function (P  <  0.001) significantly. CONCLUSIONS: This study reveals that follicles from patients with endometriosis display iron overload and lipid peroxidation, potentially contributing to diminished oocyte quality and embryonic developmental potential. These findings advance understanding of the pathophysiology of endometriosis-related infertility, and suggest that interventions targeting iron metabolism and ferroptosis may improve fertility outcomes in patients with endometriosis undergoing IVF/ICSI.