{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry, Faculty of Medicine, The Thai Red Cross Society, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Bangkok, Thailand. dr.michaelmaes@hotmail.com",
    "Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria. dr.michaelmaes@hotmail.com",
    "Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China. dr.michaelmaes@hotmail.com",
    "Kyung Hee University, Seoul, Korea. dr.michaelmaes@hotmail.com",
    "Research Center, Medical University of Plovdiv, Plovdiv, Bulgaria. dr.michaelmaes@hotmail.com",
    "Research 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. dr.michaelmaes@hotmail.com",
    "Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. dr.michaelmaes@hotmail.com",
    "Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China",
    "Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq",
    "Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China",
    "Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria",
    "Research Center, Medical University of Plovdiv, Plovdiv, Bulgaria",
    "Research 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",
    "Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China. 18190727710@163.com",
    "Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. 18190727710@163.com"
  ],
  "article_type": "review",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
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        1,
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      "name": "Michael H. J. Maes",
      "orcid": "0000-0002-2012-871X"
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      "name": "Abbas Firras Almulla",
      "orcid": "0000-0002-7667-6731"
    },
    {
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        11,
        12
      ],
      "name": "Drozdstoj Stoyanov"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Yingqiang Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/66v5v10zr9pdr.bib",
  "cited_by": 6,
  "doi": "10.1038/s41423-026-01448-1",
  "fulltext_url": null,
  "id": "66v5v10zr9pdr",
  "issns": [
    "1672-7681",
    "2042-0226"
  ],
  "landing_url": "https://doi.org/10.1038/s41423-026-01448-1",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "2803|Tryptophan and brain disorders"
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  "pdf_url": "https://www.nature.com/articles/s41423-026-01448-1.pdf",
  "pmcid": "PMC13424108",
  "pmid": "42437805",
  "published": "2026-07-13",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/66v5v10zr9pdr.ris",
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    {
      "first_seen": "2026-11-04T13:21:11Z",
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  "subjects": [
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      "field": "medicine",
      "origin": "openalex:2803|Tryptophan and brain disorders",
      "subfield": "psychiatry"
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  "title": "Unifying the hallmarks of major depression through neuroimmune–metabolic–oxidative (NIMETOX) dysregulation: a mechanistic systems framework",
  "title_text": "Unifying the hallmarks of major depression through neuroimmune–metabolic–oxidative (NIMETOX) dysregulation: a mechanistic systems framework",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:14Z",
  "url": "https://research.draconitic.com/paper/66v5v10zr9pdr",
  "venue": "Cellular and Molecular Immunology",
  "versions": []
}