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

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 variance in the overall severity of depression (74.0%), physiosomatic symptoms (58.5%), suicidal ideation (11.1%), and recurrence of illness (36.6%) was associated with the integrated metabolomics-lipidomics architecture. Conclusion The MDD lipotype indicates a unified metabolic network linked to the NIMETOX pathophysiology of MDD. Lipidomics provides a robust foundation for subtyping and precision psychiatry. Ceramide, acetyl carnitine, lipotoxicity, and plasmalogens are potential drug targets to treat MDD.