Oxylipins from n-6 and n-3 Fatty Acids Modulate Uterine Decidualization

Abstract Background Metabolic remodeling is crucial for successful decidualization, but the mechanisms coordinating the TCA cycle, fatty acids, and oxylipins with energy demands and pro-inflammatory responses during peri-implantation are unclear. Methods This study analyzed temporal metabolic changes and pro-inflammatory factors at the implantation site (IS) and inter-implantation site (IIS) from days 5 to 7 post-implantation in mice using GC–MS, UPLC-MS/MS, immunofluorescence, quantitative real-time PCR and ELISA, ANOVA, Tukey’s HSD, mixed-effects models, and Pearson’s correlation were used for statistical analysis. Results Our findings reveal dynamic metabolic changes in the IS and IIS from days 5 to 7 of pregnancy. During transition to the secondary decidual zone (SDZ), the IS exhibited metabolic adaptation, with higher TCA cycle activity compared to the IIS. On day 7, the IS also showed significantly elevated activity in the citric acid cycle, glycolysis, and pyruvate metabolism compared to day 5. Additionally,during the SDZ phase, n-3 and n-6 fatty acids and their oxylipins, particularly prostanoids like PGE2 from arachidonic acid, were upregulated in the IS, exhibiting a similar expression pattern of pro-inflammatory factors such as IL-6 and IL-8. The mRNA expression of COX-2 and mPGES-1, key enzymes related to PGE2 biosynthesis, showed a sustained increase from day 5 to day 7 of pregnancy. This suggests that PGE2 plays a key role in maintaining the pro-inflammatory environment necessary for decidualization. Conclusion This study highlights the importance of metabolic adaptations and fatty acid-derived oxylipins in ensuring energy supply and sustaining the pro-inflammatory environment during successful decidualization.