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

Lee, Chun-I; Hsu, An; Lee, Yu-Jen; Cheng, En-Hui; Lee, Chi-Ying; Lin, Pin-Yao; Lee, Maw-Sheng; Chen, Chung-I; Yu, Tzu-Ning; Wang, Tiffany; Wang, Cai-Yun; Lin, Shi-Ting; Yang, Jung-Hsuan; Hsu, Hui-Ling; Yang, Eric Pok; Lee, Tsung-Hsien

doi:10.3390/ijms27052414

Open AccessArticle

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

by

Chun-I Lee

^1,2,3,†

,

An Hsu

^4,†

,

Yu-Jen Lee

^5,6

,

En-Hui Cheng

^5,6,

Chi-Ying Lee

^5,7

,

Pin-Yao Lin

^1,6

,

Maw-Sheng Lee

^1,2,8,

Chung-I Chen

¹,

Tzu-Ning Yu

¹

,

Tiffany Wang

⁴,

Cai-Yun Wang

⁴,

Shi-Ting Lin

⁴,

Jung-Hsuan Yang

⁴,

Hui-Ling Hsu

⁴,

Eric Pok Yang

^4,* and

Tsung-Hsien Lee

^1,2,8,*

¹

Division of Infertility, Lee Women’s Hospital, Taichung 406, Taiwan

²

Department of Obstetrics and Gynecology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan

³

Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung 402, Taiwan

⁴

Inti Labs, Hsinchu 302, Taiwan

⁵

Genetic Diagnosis Laboratory, Lee Women’s Hospital, Taichung 406, Taiwan

⁶

Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 403, Taiwan

⁷

Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan

⁸

Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(5), 2414; https://doi.org/10.3390/ijms27052414

Submission received: 15 January 2026 / Revised: 2 March 2026 / Accepted: 4 March 2026 / Published: 5 March 2026

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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Abstract

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.

Keywords: peri-implantation window; microRNA; endometrium; plasma miRNA; pathway enrichment; temporal dynamics; implantation biology; systems biology

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MDPI and ACS Style

Lee, C.-I.; Hsu, A.; Lee, Y.-J.; Cheng, E.-H.; Lee, C.-Y.; Lin, P.-Y.; Lee, M.-S.; Chen, C.-I.; Yu, T.-N.; Wang, T.; et al. Pathway-Level Convergence Between Dynamic Plasma miRNAs and Endometrial Biological Processes During the Human Peri-Implantation Window. Int. J. Mol. Sci. 2026, 27, 2414. https://doi.org/10.3390/ijms27052414

AMA Style

Lee C-I, Hsu A, Lee Y-J, Cheng E-H, Lee C-Y, Lin P-Y, Lee M-S, Chen C-I, Yu T-N, Wang T, et al. Pathway-Level Convergence Between Dynamic Plasma miRNAs and Endometrial Biological Processes During the Human Peri-Implantation Window. International Journal of Molecular Sciences. 2026; 27(5):2414. https://doi.org/10.3390/ijms27052414

Chicago/Turabian Style

Lee, Chun-I, An Hsu, Yu-Jen Lee, En-Hui Cheng, Chi-Ying Lee, Pin-Yao Lin, Maw-Sheng Lee, Chung-I Chen, Tzu-Ning Yu, Tiffany Wang, and et al. 2026. "Pathway-Level Convergence Between Dynamic Plasma miRNAs and Endometrial Biological Processes During the Human Peri-Implantation Window" International Journal of Molecular Sciences 27, no. 5: 2414. https://doi.org/10.3390/ijms27052414

APA Style

Lee, C.-I., Hsu, A., Lee, Y.-J., Cheng, E.-H., Lee, C.-Y., Lin, P.-Y., Lee, M.-S., Chen, C.-I., Yu, T.-N., Wang, T., Wang, C.-Y., Lin, S.-T., Yang, J.-H., Hsu, H.-L., Yang, E. P., & Lee, T.-H. (2026). Pathway-Level Convergence Between Dynamic Plasma miRNAs and Endometrial Biological Processes During the Human Peri-Implantation Window. International Journal of Molecular Sciences, 27(5), 2414. https://doi.org/10.3390/ijms27052414

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

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