Epigenetic Landscape of Female Infertility: An Integrated Bioinformatics Perspective on DNA Methylation, MicroRNAs, and Gene Regulatory Networks Across PCOS, Endometriosis, and Diminished Ovarian Reserve

Female infertility diseases such as polycystic ovary syndrome (PCOS), endometriosis, diminished ovarian reserve (DOR), and recurrent implantation failure (RIF) have different clinical phenotypes. However, they might be epigenetically convergent, and thus the therapeutic targets may be potential. This study utilized transcriptome data, microRNA (miRNA), and DNA methylation data from the granulosa cells of four Gene Expression Omnibus (GEO) datasets, GSE138518, GSE105765, GSE232306, and GSE92324, to conduct integrated bioinformatics analysis. We focused on differentially expressed genes (DEGs), constructed a miRNA-mRNA network, performed ROC curve analysis, and conducted function enrichment and drug repurposing studies. Our findings identified eight dysregulated genes (H19, SULT1A4, HCK, SPI1, CARD16, NFE2, LST1, and KRT8) common to PCOS, DOR, and RIF, which may serve to distinguish PCOS specifically. Moreover, these DEGs are associated with pathways such as innate immune activation, inflammatory responses, the NOD-like receptor signaling pathway, and Fc gamma R-mediated phagocytosis. Notably, MiRNAs differentially expressed in endometriosis (specifically hsa-miR-202-5p and hsa-miR-141-3p) were found to directly target this gene set, highlighting the role of epigenetic regulation across infertility diseases. Additionally, our drug repurposing analysis identified several FDA-approved drugs, including Abacavir and Peginterferon Alfa-2b, suggesting that the HCK gene may be a viable target for drug development to address female infertility. Furthermore, we identified 192 genes that correlated with DNA methylation and expression levels in PCOS. Thus, this study underscores the epigenetic convergence of different female infertility diseases and highlights potential biomarkers and therapeutic options that could enhance treatment in reproductive medicine.