LRP1 as a potential diagnostic and immunomodulatory target in endometriosis: evidence from multi-omics and single-cell analyses

Endometriosis (EMS) is a common gynecological disease that seriously affects women's health and quality of life. However, the detailed dynamic cellular and molecular mechanisms underlying EMS pathogenesis remain largely unknown. This study establishes a novel diagnostic model to distinguish ectopic endometrium (EC) from eutopic endometrium (EU) samples. This study elucidated the critical role of low-density lipoprotein receptor-related protein 1 (LRP1) in EMS pathogenesis through integrated multi-omics analyses. Our comprehensive approach began with merging three GEO datasets (GSE7305, GSE11691, GSE25628), identifying 1,404 differentially expressed genes (DEGs) and 489 co-expressed genes with the brown module using weighted gene co-expression network analysis (WGCNA). A machine learning algorithm identified 30 hub genes, among which LRP1 exhibited the highest diagnostic performance. Immune profiling revealed a strong positive correlation between LRP1 and M2 macrophage infiltration (r=0.62, p<0.001), while Mendelian randomization analysis confirmed a causal relationship (OR = 1.35, 95%CI:1.13-1.61, p=0.001). Single-cell RNA sequencing demonstrated LRP1 is predominantly expressed in fibroblasts and monocytes, orchestrating cell-cell communication through the MIF signaling pathway, particularly through CD74/CXCR4 interactions. Experimental validation confirmed significantly elevated LRP1 expression in ectopic lesions at both mRNA (p<0.01) and protein levels. Mechanistically, LRP1 may promote the progression of EMS by enhancing cell migration, invasion, and proliferation through the MIF signaling pathway. Collectively, these findings identified LRP1 as a central regulator of EMS progression through immunomodulation and intercellular crosstalk, offering novel diagnostic and therapeutic potential.