SLC7A11-Mediated Glutathione Synthesis and the Pentose Phosphate Pathway: A Novel Anti-Oxidative Mechanism in Decidualization

Oxidative damage is a common occurrence in reproductive system diseases, often leading to infertility. Depending on the severity, abnormal decidualization can result in implantation failure, early pregnancy loss, or an increased risk of obstetric complications related to impaired placental function, such as preeclampsia, fetal growth restriction, and preterm delivery. However, the relationship between oxidative damage and abnormal decidualization is not well understood. This study provides direct evidence of a decrease in reactive oxygen species (ROS) during the decidualization of stromal cells and an increase in SLC7A11-mediated glutathione synthesis. Additionally, our investigation reveals an increased flux of the pentose phosphate pathway in glucose metabolism during the decidualization of stromal cells. Notably, the enzyme glucose-6-phosphate dehydrogenase (G6PD) within this pathway generates the necessary reducing equivalent, NADPH, for glutathione synthesis regulated by SLC7A11.

Furthermore, stromal cells upregulate the metabolic flux of the pentose phosphate pathway and its key enzyme, glucose-6-phosphate dehydrogenase (G6PD), during decidualization. This modulation of glucose metabolism allows for the production of NADPH, which is required for glutathione synthesis. This reprogramming of glucose metabolism, regulated by SLC7A11, has been observed in various studies focusing on tumors.

After an increase in progesterone levels following ovulation, the endometrium becomes receptive to embryo implantation during the midluteal phase of the menstrual cycle. This implantation window marks the beginning of extensive tissue remodeling, driven by the differentiation of endometrial stromal cells (EnSC) into decidual cells (DC). This differentiation process is accompanied by a surge in reactive oxygen species (ROS) and the release of proinflammatory cytokines, which are characteristic of an evolutionarily conserved acute cellular stress response. Decidual cells are known for their resistance to various stress signals, including oxidative stress. This resistance is achieved through the upregulation of oxidative stress defense proteins and the production of ROS scavengers. The impact of ROS on decidualization is complex, as the initial stage of decidualization is characterized by a significant increase in ROS levels, which may positively correlate with stromal cell differentiation. However, our results demonstrate that as decidualization progresses, the ROS levels in decidual cells are significantly lower than those in undifferentiated stromal cells, potentially indicating a negative effect of ROS on decidual cell function. These findings align with conclusions drawn from multiple recent studies in the same research field. Similarly, artificially increasing ROS levels through hydrogen peroxide impairs decidualization.

This study is the first to focus on and confirm the anti-oxidative stress effect of the SLC7A11 molecule during decidualization. While previous research has suggested various antioxidant mechanisms for endometrial stromal cells, none have focused on the glutathione synthesis phenotype during this process. In tumor research, SLC7A11 is widely recognized as a crucial molecule in the modulation of glutathione synthesis, which is associated with cellular resistance against oxidative stress and the amelioration of lipid peroxidation. Recent investigations have shown that the transcription factor NRF2 plays a crucial role in the regulation of SLC7A11. This discovery has sparked interest in exploring the role of SLC7A11 in decidualization, especially considering the established upstream regulatory function of NRF2 in decidualization.

Increasing evidence suggests that many cells undergo metabolic reprogramming during the differentiation process, with glucose serving as a fundamental metabolite for maintaining cellular functions. Numerous studies have shown that tumor cells with high SLC7A11 expression heavily rely on glucose supply for growth. Therefore, after establishing the key role of SLC7A11 in decidualization and antioxidation, it is logical to hypothesize that glucose metabolism may be involved in the decidualization process.

Decidualization is a unique differentiation phenotype of endometrial stromal cells. During this process, there are multidimensional changes in nutrient metabolism, including alterations in lipid metabolism, amino acid metabolism, and glucose metabolism to varying degrees. Previous studies have mainly focused on changes in glycolysis and the tricarboxylic acid cycle in endometrial stromal cells during decidualization, particularly glycolysis. Key enzymes in glycolysis, such as hexokinase, pyruvate kinase, and lactate dehydrogenase, as well as core products pyruvate and lactate, have been positively correlated with decidualization. Our research introduces a novel concept: during decidualization, the pentose phosphate pathway of glucose metabolism also plays a critical role alongside the classical glycolytic metabolic pathway. This pentose phosphate pathway is essential for maintaining the antioxidative stress capacity of stromal cells throughout the decidualization process. Through radioactive isotope-labeled glucose-targeted metabolomics, we discovered that the intermediates of the pentose phosphate pathway in stromal cells increased after decidualization induction, and the proportion of the final product, M1-type lactic acid produced by the pentose phosphate pathway, also increased. These findings reveal that the metabolic flux of the pentose phosphate pathway intensifies during decidualization.

The primary function of the pentose phosphate pathway is to provide NADPH as a reducing equivalent, a reaction facilitated by G6PD. Recent research has shifted the understanding of NADPH's role in decidualization. Some studies suggest that NADPH may contribute to and facilitate the decidualization process by acting as an antioxidant. Our study concludes that NADPH suppresses ROS levels during decidualization, rather than promoting ROS generation, and this effect is achieved by facilitating glutathione synthesis. Similar results have been observed in related studies involving tumor cells with high SLC7A11 expression.

Our research primarily focuses on the physiological process of decidualization and has not been directly linked to clinical diseases. However, it is important to consider that bioinformatics research has suggested potential associations between SLC7A11 and various reproductive disorders, such as recurrent miscarriage. Therefore, future studies should investigate the relationship between reproductive diseases and SLC7A11, with a focus on more precise signaling pathways. These two biochemical pathways, the pentose phosphate pathway and glutathione synthesis, deserve further attention to clarify their roles in diseases resulting in abnormal decidualization, which may provide new insights for disease treatment.