Pathway-Level Convergence Between Dynamic Plasma miRNAs and Endometrial Biological Processes During the Human Peri-Implantation Window

The peri-implantation window is a tightly regulated temporal phase during which the human endometrium undergoes coordinated molecular remodeling to establish receptivity. MicroRNAs (miRNAs) contribute to implantation-related processes; however, whether dynamic endometrial regulatory signals are functionally reflected in circulation within a defined temporal framework remains unclear. We hypothesized that although individual miRNA identities differ between endometrial tissue and plasma, temporally regulated miRNAs in both compartments may exhibit overlap at the level of enriched biological pathways during the peri-implantation window. To test this hypothesis, we performed time-resolved small RNA sequencing on paired endometrial and plasma samples collected from 62 participants across progesterone exposure days P+3 to P+7 in hormonally controlled cycles. Temporal modeling identified 27 dynamic miRNAs in endometrial tissue and 17 in plasma (FDR < 0.05). Despite limited overlap at the individual miRNA level, functional enrichment analysis revealed recurrent overlap in apoptosis-, cell cycle-, aging-, inflammatory-, and metabolic-related pathways across compartments. Four miRNAs exhibited concordant directional temporal trends between tissue and plasma with moderate correlation coefficients. These findings suggest that dynamic miRNA-associated enrichment patterns during the peri-implantation window may exhibit pathway-level overlap despite divergence in specific molecular identities. This temporally aligned integrative framework provides a pathway-centric perspective for interpreting cross-compartment miRNA-associated temporal patterns and supports a hypothesis-generating systems-level view of human implantation biology.