Deciphering the Role of Plasma Lipids in Pre-eclampsia and Eclampsia: Insights from Mendelian Randomization, Network Toxicology, and Molecular Dynamics Simulations

Abstract Objective This study aims to explore the mechanistic roles of the plasma lipidome in pre-eclampsia and eclampsia by integrating Mendelian randomization, network toxicology, and molecular dynamics simulation approaches. Methods Summary statistics for 179 lipid species, pre-eclampsia, eclampsia, and hypertension-related phenotypes were obtained from large-scale genome-wide association studies. A two-sample Mendelian randomization (MR) analysis was performed using inverse-variance weighting (IVW) as the primary method. Network toxicology was used to generate potential mechanistic hypotheses, while molecular docking and molecular dynamics simulations were performed to assess the structural feasibility and simulated stability of interactions between the selected Triacylglycerol (50:1) structure and PPARA/PPARG. Results The findings revealed significant associations between 16 plasma lipid species and pre-eclampsia, while 8 lipids showed positive or negative causal relationships with eclampsia. Additionally, 14 plasma lipids were significantly associated with hypertension, as indicated by the specific ranges of IVW-OR values (all P < 0.05). Notably, triacylglycerol (50:1) levels were positively correlated with the risk of pre-eclampsia, eclampsia, and hypertension, whereas phosphatidylethanolamine (O-16:1_18:2) levels exhibited opposite associations with pre-eclampsia and eclampsia. Although triacylglycerol (54:3) levels were positively associated with both pre-eclampsia and hypertension, pleiotropy was observed in the hypertension results. Network toxicology analysis identified 51 intersecting genes of triacylglycerol (50:1) with pre-eclampsia and eclampsia. Protein–protein interaction (PPI) network analysis highlighted prostaglandin-endoperoxide synthase 2 (PTGS2), peroxisome proliferator activated receptor gamma (PPARG), peroxisome proliferator activated receptor alpha(PPARA), Jun proto-oncogene, AP-1 transcription factor subunit (JUN), and nuclear receptor subfamily 3 group C member 1 (NR3C1) as hub targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that triacylglycerol (50:1) may contribute to pre-eclampsia and eclampsia through the PPAR signaling pathway. Molecular docking identified structurally plausible interaction poses between the selected Triacylglycerol (50:1) structure and PPARA/PPARG, and the modeled complexes remained relatively stable during the 100-ns molecular dynamics simulations under the specified computational conditions. Conclusion This study provides novel evidence linking plasma lipid profiles to the pathogenesis of pre-eclampsia and eclampsia. Triacylglycerol (50:1) emerged as a lipid species genetically associated with increased risks of pre-eclampsia, eclampsia, and hypertension. Network-based analyses suggested a potential link with the PPAR signaling pathway, while molecular docking and molecular dynamics simulations supported the structural feasibility of interactions between the selected Triacylglycerol (50:1) structure and PPARA/PPARG. These in silico findings generate a testable mechanistic hypothesis but do not independently establish receptor activation or functional regulation. Further biochemical and experimental validation is therefore required.