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This review aims to consolidate existing knowledge on the neuroimmune, metabolic, and oxidative factors contributing to major depressive disorder.

July 14, 2026Cellular and Molecular Immunology0 citationsOpen Access

Unifying the hallmarks of major depression through neuroimmune–metabolic–oxidative (NIMETOX) dysregulation: a mechanistic systems framework

MMMichaël MaesUniversity of Electronic Science and Technology of China AAAbbas F. AlmullaUniversity of Electronic Science and Technology of China DSDrozdstoj StoyanovMedical University Plovdiv

Key Points

This review aims to consolidate existing knowledge on the neuroimmune, metabolic, and oxidative factors contributing to major depressive disorder.
Analyzed clinical literature from 1990 to 2026 relating to MDD and NIMETOX pathways.
Examined immune alterations, metabolic dysfunctions, and oxidative stress mechanisms.
Utilized deep phenotyping, panomics methodologies, and machine learning for data integration.
Documented immune sensitization and dysregulation in MDD with effects on lipid metabolism and neuroprotection.
Identified interactions between oxidative stress, metabolic syndrome, and atherogenicity causing neuronal damage.
Proposed that NIMETOX pathways from immune cells contribute to neuroinflammation and impair brain function.

Abstract

Abstract Current state-of-the-art neuroimmune, metabolic, and oxidative stress (NIMETOX) knowledge that has been developed in clinical major depressive disorder (MDD) research over the past three decades is explored in this review. Between 1990 and 2000, the acute phase of severe MDD was characterized by the activation of T helper (Th)1 cells and M1 macrophages, leading to immune dysregulation that affects nutritional immunity and alters protein, tryptophan, iron, and lipid metabolism. The latter comprises lower high-density lipoprotein cholesterol, reverse cholesterol transport (RCT), ω3 polyunsaturated fatty acids, heightened lipid peroxidation and atherogenicity. Additionally, immune alterations regulate stress-responsive systems and modify the biological basis of depressive symptoms through neurotoxic effects and reduced neuroprotection. The incremental information acquired from 2000 to 2026 revealed that the acute phase of severe MDD is characterized by immune sensitization, imbalances between the compensatory immunoregulatory system (CIRS) and the immune-inflammatory response system (IRS) and that there are multiple interactions between increased atherogenicity, metabolic syndrome, oxidative stress, and lower antioxidant activity and RCT. Additionally, the NIMETOX pathway may be fuelled by increased expression of TLR4 and NF-κB intracellular signaling driven by increased lipopolysaccharides, lipids, and oxidatively modified epitopes. This paper presents evidence that peripheral NIMETOX pathways may lead to neuroinflammation, microglial activation, and neuronal damage and that increased lipid load impairs these central pathways. This paper assesses the field’s future advancements by conducting a comprehensive examination of the reviewed knowledge base, deep phenotyping, panomics methodologies, and machine learning techniques, including the nomothetic precision approach.

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