Ether-linked phospholipidomic profiling unveils novel lipid fingerprints and algorithm predicts the future development of carotid plaques in postmenopausal women: a population-based cohort study

Background Serum ether-linked phospholipids (ePLs) have gained attention in metabolic disease research. Postmenopausal women face a higher risk of developing atherosclerosis (AS), yet current methods for risk prediction and understanding of AS pathophysiology remain limited. This study aimed to identify ePL biomarkers linked to AS, assess their chemical composition in relation to AS risk, and explore whether their impact is mediated by clinical risk factors in postmenopausal women. Methods Here, this research was conducted within the Rose Asymptomatic Intracranial Artery Stenosis (RICAS) prospective study and included 203 postmenopausal women without carotid plaques at baseline. After a median follow-up of 3.8 years, 51 participants developed new carotid plaques. Baseline serum ePLs were semi-quantitated using liquid chromatography-mass spectrometry. Results The mean age of participants was 60.51 (±7.83) years. A total of 85 unique ePL species across five lipid subclasses were identified and quantified according to lipid internal standards. Multivariate models indicated global metabolic disruptions in ePLs preceding carotid plaque formation. Six ePLs were identified as potential biomarkers associated with AS risk (VIP > 1, p < 0.05, FDR < 0.05). After adjusting for age, BMI, TG, and LDL-C, four polyunsaturated fatty acid (PUFA)-containing ePLs remained significantly associated with carotid plaque risk (OR > 1, p < 0.05). Causal mediation analysis indicated that LDL-C mediated the effects of these ePLs on AS. A machine-learning model incorporating these ePLs with clinical parameters significantly improved carotid plaque prediction (AUC: 0.835, Net Reclassification Improvement > 0, p < 0.001). Conclusion This study highlighted importance of metabolic disruption in PUFA-ePLs for the development of AS. Our findings support the notion that metabolic disruption of PUFA-ePLs can affect LDL-C levels, which is the primary driver of AS in postmenopausal women. Ether-linked phospholipidome as a valuable phenotype hold potential clinical utility in the prediction of AS.