Deep Lipidomic Phenotyping Identifies Ceramide-Centered Lipotoxicity and Depletion of Plasmalogen-Carnitine Pathways in Major Depressive Disorder: Implications for Precision Medicine

作者：Yingqian Zhang, Xi Zhang, Mengqi Niu, Yiping Luo, Abbas F. Almulla, Annabel Maes, Jin Li, Bo Zhou, Michael Maes · 发表于：medRxiv · 年份：2026 · DOI：10.64898/2026.02.01.26345328 · 被引用次数：3 · 研究领域：Tryptophan and brain disorders、Metabolomics and Mass Spectrometry Studies、Gut microbiota and health

Abstract Background Major depressive disorder (MDD) severely impairs individual health and creates heavy societal burdens. Diagnostic and therapeutic research remains hindered by MDD’s marked heterogeneity and the absence of valid biomarkers. As a neuro-immune, metabolic, and oxidative stress (NIMETOX) disorder, MDD exhibits metabolomic signatures as a final common pathway in the Chinese population. Objectives To identify lipidomic profile differences between MDD patients and healthy controls and examine associations between lipidomic alterations and clinical phenotypes. Methods We recruited 125 MDD patients and 40 healthy controls, and measured serum lipidomic profiles using liquid chromatography-mass spectrometry. A rigorously controlled multistage machine learning pipeline with leakage-prevention measures was utilized to examine disparities between MDD and control groups and to predict phenome features. Results We identified 43 differentially abundant lipids between the MDD and control groups. Subsequent factor analysis clustered the 43 lipids into 3 functional modules, namely the increased ceramide/GM3/LNAPE (CERLNAPE) module, the decreased mitochondrial fatty acid oxidation/acetyl-flux (CARSM) module, and the reduced lysophospholipid/ether-lysolipid (LYSOPE) module. The three lipidomic modules correlated with six previously reported metabolomic functional domains, establishing an integrated metabolomics-lipidomics architecture in MDD. A substantial portion of the varianc...