Fructose-1,6-bisphosphate prevents pregnancy loss by inducing decidual COX-2⁺ macrophage differentiation

Decidualization is an intricate biological process in which extensive remodeling of the endometrium occurs to support the development of an implanting blastocyst. However, the immunometabolic mechanisms underlying this process are still largely unknown. We found that the decidualization process is accompanied by the accumulation of fructose-1,6-bisphosphate (FBP). The combination of FBP with pyruvate kinase M stimulated IL-27 secretion by endometrial stromal cells in an ERK/c-FOS-dependent manner. IL-27 induced decidual COX-2⁺ M2-like macrophage differentiation, which promotes decidualization, trophoblast invasion, and maternal-fetal tolerance. Transfer of Ptgs2⁺/COX-2⁺ macrophages prevented fetal loss in Il27ra-deleted pregnant mice. FBP levels were low in plasma and decidual tissues of patients with unexplained recurrent spontaneous abortion. In therapeutic studies, FBP supplementation significantly improved embryo loss by up-regulation of IL-27-induced COX-2⁺ macrophage differentiation in a mouse model of spontaneous abortion. These findings collectively provide a scientific basis for a potential therapeutic strategy to prevent pregnancy loss.