Molecular subtype of recurrent implantation failure reveals distinct endometrial etiology of female infertility

作者：Jing Yang, Lingtao Yang, Ying Zhou, Fengyang Cao, Hongkun Fang, Huan Ma, Jun Ren, Chunyu Huang, Lianghui Diao, Qiyuan Li, Qionghua Chen · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06771-1 · 被引用次数：13 · 研究领域：Reproductive System and Pregnancy、Endometriosis Research and Treatment、Gynecological conditions and treatments

BACKGROUND: Recurrent implantation failure (RIF) remains a significant barrier in assisted reproductive technology (ART), where multiple transfers of high-quality embryos fail to achieve pregnancy. While embryo-related factors have been extensively investigated, the contribution of endometrial dysfunction to RIF remains poorly characterized. This study aimed to determine whether biologically distinct molecular subtypes of endometrial dysfunction exist in RIF and whether such subtypes could guide more personalized and effective treatment strategies. METHODS: We conducted a comprehensive computational analysis integrating publicly available endometrial transcriptomic datasets with prospectively collected samples. Multi-platform data were harmonized using a random-effects model. Differentially expressed genes (DEGs) between RIF and normal samples were identified using MetaDE. Clinical and hormonal correlations were used to assess heterogeneity among RIF samples. Unsupervised clustering (ConsensusClusterPlus) identified RIF subtypes, and their biological characteristics were analyzed using Gene Set Enrichment Analysis (GSEA). Immunohistochemistry (IHC) was used to evaluate the protein-level expression of selected subtype-associated genes. A molecular classifier (MetaRIF) was developed using the optimal F-score from 64 combinations of machine learning algorithms. Candidate therapeutic compounds were predicted using the Connectivity Map (CMap) database. RESULTS: A total of 1,776 ro...