Excessive Lipid Peroxidation in Uterine Epithelium Causes Implantation Failure and Pregnancy Loss

Abstract The uterine epithelium undergoes a dramatic spatiotemporal transformation to enter a receptive state, involving a complex interaction between ovarian hormones and signals from stromal and epithelial cells. Redox homeostasis is critical for cellular physiological steady state; emerging evidence reveals that excessive lipid peroxides derail redox homeostasis, causing various diseases. However, the role of redox homeostasis in early pregnancy remains largely unknown. It is found that uterine deletion of Glutathione peroxidase 4 (GPX4), a key factor in repairing oxidative damage to lipids, confers defective implantation, leading to infertility. To further pinpoint Gpx4 ’s role in different cell types, uterine epithelial‐specific Gpx4 is deleted by a lactotransferrin (Ltf) ‐ Cre driver; the resultant females are infertile, suggesting increased lipid peroxidation levels in uterine epithelium compromises receptivity and implantation. Lipid peroxidation inhibitor administration failed to rescue implantation due to carbonylation of major receptive‐related proteins underlying high lipid reactive oxygen species. Intriguingly, superimposition of Acyl‐CoA synthetase long‐chain family member 4 (ACSL4), an enzyme that promotes biosynthesis of phospholipid hydroperoxides, along with uterine epithelial GPX4 deletion, preserves reproductive capacity. This study reveals the pernicious impact of unbalanced redox signaling on embryo implantation and suggests the obliteration of lipid peroxides as a possible therapeutic approach to prevent implantation defects.