Causal links and mediating effects of lipid metabolism, immune cells, and inflammatory proteins in endometriosis: Evidence from Mendelian randomization.

Abstract

Endometriosis (EMS) is a complex gynecological disorder whose pathogenesis remains poorly understood, with lipid metabolism, immune regulation, and inflammation likely playing pivotal roles. This Mendelian randomization study investigates causal relationships between lipid metabolic levels, immune cell characteristics, inflammatory proteins, and EMS using multi-omics data from 179 lipid metabolites, 731 immune cell traits, and 91 inflammatory proteins, combined with EMS cases from the FinnGen database. Sensitivity analyses were conducted using inverse variance weighted, Mendelian randomization Egger regression, weighted median, and weighted mode methods to ensure robust findings. Our analysis identified significant associations between 21 lipid metabolites and EMS, with 9 metabolites showing protective effects and 12 promoting risk. Specifically, triacylglycerol (46:2) levels displayed a reverse causal relationship with EMS. Additionally, 32 immune cell traits and 6 inflammatory proteins were linked to EMS risk, with IL-17A, TNF-related apoptosis-inducing ligand, and C-C motif chemokine 4 emerging as key inflammatory proteins. Notably, IL-17A was positively correlated with EMS progression, while TNF-related apoptosis-inducing ligand and C-C motif chemokine 4 exhibited protective effects. Mediation analysis further uncovered pathways where lipid metabolites modulate immune responses and inflammatory proteins, influencing EMS development. These findings suggest that lipid metabolism, immune traits, and inflammatory proteins may contribute to EMS pathogenesis, offering initial insights into potential mechanisms. Further experimental validation is needed to corroborate these results.