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Peer-reviewedCC BYCellular and Molecular Immunology

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

  • Michael H. J. Maes1,2,3,4,5,6,7
  • Abbas Firras Almulla8,9,10
  • Drozdstoj Stoyanov11,12,13
  • Yingqiang Zhang14,15
15 affiliations
  1. 1Department of Psychiatry, Faculty of Medicine, The Thai Red Cross Society, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Bangkok, Thailand. [email protected]
  2. 2Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria. [email protected]
  3. 3Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China. [email protected]
  4. 4Kyung Hee University, Seoul, Korea. [email protected]
  5. 5Research Center, Medical University of Plovdiv, Plovdiv, Bulgaria. [email protected]
  6. 6Research and Innovation Program for the Development of MUs - PLOVDIV- (SRIPD-MUP), Creation of a network of research higher schools, National plan for recovery and sustainability, European Union - NextGenerationEU, Plovdiv, Bulgaria. [email protected]
  7. 7Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [email protected]
  8. 8Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China
  9. 9Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
  10. 10Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
  11. 11Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
  12. 12Research Center, Medical University of Plovdiv, Plovdiv, Bulgaria
  13. 13Research and Innovation Program for the Development of MUs - PLOVDIV- (SRIPD-MUP), Creation of a network of research higher schools, National plan for recovery and sustainability, European Union - NextGenerationEU, Plovdiv, Bulgaria
  14. 14Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China. [email protected]
  15. 15Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [email protected]
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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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Cite

BibTeXRIS
BibTeX
@article{maes2026unifying,
  title = {{Unifying the hallmarks of major depression through neuroimmune–metabolic–oxidative (NIMETOX) dysregulation: a mechanistic systems framework}},
  author = {Michael H. J. Maes and Abbas Firras Almulla and Drozdstoj Stoyanov and Yingqiang Zhang},
  journal = {Cellular and Molecular Immunology},
  year = {2026},
  month = jul,
  doi = {10.1038/s41423-026-01448-1},
  url = {https://doi.org/10.1038/s41423-026-01448-1},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Unifying the hallmarks of major depression through neuroimmune–metabolic–oxidative (NIMETOX) dysregulation: a mechanistic systems framework
AU  - Michael H. J. Maes
AU  - Abbas Firras Almulla
AU  - Drozdstoj Stoyanov
AU  - Yingqiang Zhang
PY  - 2026
DA  - 2026/07/13
JO  - Cellular and Molecular Immunology
DO  - 10.1038/s41423-026-01448-1
UR  - https://doi.org/10.1038/s41423-026-01448-1
AB  - 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.
SN  - 1672-7681
SN  - 2042-0226
ER  -