Exosome-Related Pathogenic Genes in Adenomyosis: A Multi-Omics Mendelian Randomization Study.

This study employed a multi-omics Mendelian randomization (MR) framework to identify exosome-related genes potentially associated with adenomyosis risk. We integrated adenomyosis Genome-Wide Association Study data with blood-based methylation (mQTL), expression (eQTL), and protein (pQTL) quantitative trait loci, followed by Summary-data-based Mendelian Randomization (SMR), heterogeneity in dependent instruments and colocalization analysis. To address tissue specificity, a sensitivity analysis using GTEx uterus eQTL data was performed. Results were subsequently validated using endometrial transcriptomic data (GSE185392). Functional enrichment, drug prediction, and molecular docking analyses were also performed. Integrated SMR and colocalization identified multiple molecular traits linked to adenomyosis risk. Cross-validation with the GEO (gene expression omnibus) dataset suggested seven key exosome-related genes-ACTR1B, ARF5, CKAP4, PTPRF, RAC1, SFRP1, and UBE2G-demonstrating consistent associations across genetic and transcriptomic levels. Functional enrichment revealed these genes are primarily involved in wound healing, exosome biogenesis, and PI3K signaling pathways. Notably, drug prediction and molecular docking showed that doxycycline exhibits strong binding affinity to the SFRP1 (affinity = -10.6 kcal·mol-1), suggesting a potential candidate for further investigation. In conclusion, this study identifies seven exosome-related genes with causal evidence for adenomyosis risk, supported by multi-omics and transcriptomic validation. These findings provide novel insights into the molecular etiology of adenomyosis and suggest specific targets for future functional validation.