Successful pregnancy depends on precise molecular regulation of uterine physiology, especially during the menstrual cycle. Deregulated oxidative stress (OS), often influenced by inflammatory changes but also by environmental factors, represents a constant threat to this delicate balance. Oxidative stress induces a reciprocally regulated nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor-gamma (Nrf2/PPARγ) pathway. However, increased PPARγ activity appears to be a double-edged sword in endometrial physiology. Activated PPARγ attenuates inflammation and attenuates OS to restore redox homeostasis. However, it also interferes with physiological processes during the menstrual cycle, such as hormonal signaling and angiogenesis. This review provides an elucidation of the molecular mechanisms that support the interplay between PPARγ and OS. Additionally, it offers fresh perspectives on the Nrf2/PPARγ pathway concerning endometrial receptivity and its potential implications for infertility.

Infertility affects millions worldwide, and implantation failure remains a critical barrier in assisted reproduction. Endometrial receptivity, a fundamental prerequisite for successful implantation, involves precise regulation of extracellular matrix components, with hyaluronan (HA) being particularly significant due to its structural and signaling roles. This study evaluated the expression of genes involved in HA metabolism and regulation across different phases of the menstrual cycle, particularly emphasizing their role during the window of implantation in normal fertility and repeated in vitro fertilization failures. Analysis of publicly available transcriptomic datasets revealed distinct expression patterns of HA synthases (HAS2, HAS3), HA-degrading enzymes (HYAL2, CEMIP, CEMIP2), and HA receptors (CD44, RHAMM, layilin) in endometrium that dynamically change toward the receptive state. Notably, HAS enzymes and HA receptors were upregulated during the mid-secretory phase, whereas classical HA-degrading enzymes showed complex regulation, suggesting a balance between HA synthesis and degradation necessary for optimal endometrial function. In patients with repeated IVF failure, there was significant downregulation of key HA-related genes (HAS2, HAS3, CEMIP, CD44, versican, syndecans), implicating impaired HA metabolism in implantation failure. The results underscore the role of HA metabolism and HA receptors in establishing a receptive endometrial environment, highlighting HA and its associated pathways as potential therapeutic targets to enhance reproductive success rates. Further research is necessary to unravel the detailed molecular mechanisms of HA-mediated regulation and its translational implications for assisted reproduction technologies.