Exploring novel molecular mechanisms underlying recurrent pregnancy loss in decidual tissues

Recurrent pregnancy loss (RPL), which affects approximately 2.5% of reproductive-aged women, remains idiopathic in more than 50% of cases, necessitating mechanistic insights and biomarkers. Three RPL decidual tissue transcriptomic datasets (GSE113790, GSE161969, and GSE178535) were integrated for differential expression, weighted gene co-expression network analysis (WGCNA), and functional enrichment analyses. Machine learning (LASSO, SVM-RFE, RF) identified optimal feature genes, which were validated via real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Immune infiltration was assessed using single-sample gene set enrichment analysis(ssGSEA). In vitro experiments evaluated the role of Complement Factor H-Related Protein 1 (CFHR1) in decidualization and the complement/coagulation pathways. Ten key genes were identified, with CFHR1 emerging as the optimal biomarker. CFHR1 overexpression correlated with complement/coagulation dysregulation and impaired decidualization. Immune profiling demonstrated increased numbers of macrophages and γδ T cells in RPL decidua, with macrophage levels showing a significant positive correlation with CFHR1(r = 0.64, p < 0.01). ROC analysis demonstrated the diagnostic efficacy of CFHR1 (AUC = 0.950). CFHR1drives RPL pathogenesis through complement/coagulation activation and immunemicroenvironment remodeling. Its role as a multifunctional mediator highlights itstherapeutic potential, suggesting novel targets for clinical intervention.