ArticleActa neuropsychiatrica2026
Peripheral metabolic-redox signaling as a core mechanism of major depressive disorder: evidence from deep metabolomic phenotyping.
Article in Acta neuropsychiatrica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Unifying the hallmarks of major depression through neuroimmune-metabolic-oxidative (NIMETOX) dysregulation: a mechanistic systems framework.Cellular & molecular immunology · 2026Review
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8 authors.
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Abstract
backgroundMajor depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile.
objectivesTo identify metabolic abnormalities that differentiate in patients with severe MDD from healthy controls(HCs) through high-resolution, untargeted metabolomics.
methodsSerum samples from 125 MDD inpatients and 40 HCs were analyzed utilizing liquid chromatography(LC) and mass spectrometry(MS). A meticulously regulated multistage machine-learning pipeline with leakage-prevention protocols was employed to analyze differences between MDD and controls and to predict phenome scores.
resultsFeature selection showed that 16 metabolites and 6 functional modules reliably distinguished MDD. The functional profile of the metabolites indicates a convergence of lipotoxicity, phospholipid(PL) remodeling, disruptions in fatty acid(FA) metabolism, mitochondrial redox imbalance, ether-lipid metabolism, and antioxidant depletion. This MDD metabotype was not affected by metabolic syndrome(MetS). A substantial portion of the variance in overall depression severity (72.5%), physiosomatic symptoms (55.8%), and suicidal ideation(SI) (23.6%) was accounted for by increased lipotoxicity, PL remodeling, and FA storage/signaling. The recurrence of illness (27.7%) was associated with a self-reinforcing lipid-redox-inflammatory module that maintains cellular stress. DISCUSSION: The MDD metabotype represents a cohesive metabolic network that is associated with the NIMETOX pathogenesis of MDD. Metabolomics provides a comprehensive foundation for subtyping and precision psychiatry. Lipoxygenase-15, lipotoxicity, phospholipase A
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