Protective Role of Slc7a11 in Decidualization: Insights into Anti-Oxidative Stress Support Through the Pentose Phosphate Pathway

Decidualization is the differentiation process whereby fibroblast-like endometrial stromal cells transform into secretory-like decidual cells. Normal decidualization is essential for successful embryo implantation and proper formation of the placenta. Abnormal decidualization, often resulting from redox imbalances, is associated with infertility in reproductive-related diseases. Our study aims to elucidate the anti-oxidative stress mechanism during decidualization, involving the glutathione antioxidant system mediated by SLC7A11. Elevated levels of oxidative stress can impair decidualization. As stromal cells undergo decidualization, the level of reactive oxygen species decreases, and the capacity to resist oxidative stress increases. This process is related to the synthesis of glutathione in stromal cells. We demonstrated that the pentose phosphate pathway in glucose metabolism is a crucial metabolic process for decidualization of stromal cells, as evidenced by targeted glucose flux assays. The pentose phosphate pathway provides NADPH required for glutathione synthesis, which is regulated by the key enzyme glucose-6-phosphate dehydrogenase (G6PD), enabling stromal cells to resist oxidative stress during decidualization. Inhibition of glutathione synthesis or the G6PD impairs the decidualization of stromal cells both in vitro and in vivo. In conclusion, our study elucidates the crucial role of SLC7A11-mediated glutathione synthesis in stromal cells, emphasizing its significance in safeguarding against oxidative stress during decidualization. Furthermore, our findings highlight the importance of the pentose phosphate pathway in glucose metabolism, especially its key enzyme G6PD, for the decidualization process. Consequently, targeting glutathione synthesis or supplementing the pentose phosphate pathway may represent a novel therapeutic strategy for infertility diseases associated with impaired decidualization.