SLC7A11 and Pentose Phosphate Pathway Cooperate to Regulate Oxidative Stress during Endometrial Decidualization

Our study provides direct evidence of a novel mechanism regulating oxidative stress during endometrial decidualization. We discovered that as endometrial stromal cells undergo decidualization, intracellular oxidative stress levels decrease, while the expression of the transporter protein SLC7A11, responsible for cystine transport into cells, significantly increases. Inhibiting SLC7A11 expression in endometrial stromal cells using SLC7A11-specific siRNA significantly inhibits the decidualization induction process. We hypothesize that the elevation of SLC7A11 during decidualization may lead to increased cystine uptake, which, in turn, promotes the production of glutathione via NADPH reduction, thereby lowering intracellular ROS levels. Our findings also revealed that the pentose phosphate pathway is activated during decidualization, with a notable increase in sugar metabolites associated with NADPH synthesis. Inhibiting the expression of the rate-limiting enzyme G6PD in the pentose phosphate pathway significantly hampers decidualization changes in endometrial stromal cells. Furthermore, we observed that decidualization induction is hindered in the absence of glucose, but this inhibition can be reversed by adding NADPH, cystine, or glutathione. We speculate that glucose deficiency results in insufficient NADPH synthesis, leading to a decline in intracellular antioxidant levels, ultimately hindering decidualization induction. This research unveils a groundbreaking discovery: the concerted action of SLC7A11-mediated cystine transport and NADPH generation through the pentose phosphate pathway is a key mechanism governing endometrial stromal cell decidualization. These findings provide a theoretical framework for understanding pathological processes such as endometrial-related infertility. \\ Our research provides experimental evidence for the changes in ROS levels during endometrial decidualization and the pivotal roles of SLC7A11 and the pentose phosphate pathway in this process. These discoveries offer fresh insights into our understanding of oxidative stress regulation mechanisms during endometrial decidualization. Firstly, we observed a decrease in intracellular ROS levels during decidualization, aligning with previous research findings. Additionally, our study revealed a significant increase in SLC7A11 expression during decidualization, which may contribute to the reduction of intracellular ROS levels by enhancing glutathione synthesis. Moreover, our research demonstrated that the pentose phosphate pathway is activated during decidualization, accompanied by a noticeable increase in sugar metabolites associated with NADPH synthesis. Finally, our investigation uncovered that glucose deficiency hampers decidualization induction in endometrial stromal cells, but this inhibition can be reversed by supplementing with NADPH, cystine, or glutathione. These discoveries shed light on the key regulatory mechanisms involved in endometrial decidualization and offer novel avenues for further research into diseases such as endometrial-related infertility. \\ Our research holds significant clinical implications. Oxidative damage is prevalent in reproductive system diseases, often leading to infertility. Abnormal decidualization can lead to implantation failure, early pregnancy loss, or predisposition to obstetrical complications associated with impaired placental function, such as preeclampsia, fetal growth restriction, and preterm delivery. However, the relationship between oxidative damage and abnormal decidualization remains unclear. Our study provides the first direct evidence for the decrease in ROS and the increase in SLC7A11-mediated glutathione synthesis during decidualization. Additionally, our research