{
  "abstract": "While Western dietary patterns are increasingly linked to neuropsychiatric disorders, the causal mechanisms by which chronic high-fat diet (HFD) contributes to depression remain elusive. Here, we demonstrate that prolonged ( ≥ 10 weeks) HFD exposure in mice robustly induces depressive-like behaviors, phenocopying chronic stress models. Integrating multi-omics and targeted lipidomics, we reveal that HFD-induced behavioral deficits are underpinned by gut microbiota dysbiosis and a profound disruption of polyunsaturated fatty acid (PUFA) homeostasis. This disruption is characterized by a surge in pro-inflammatory ω-6 metabolites, particularly arachidonic acid (AA), alongside a concomitant reduction in anti-inflammatory ω-3 metabolites. These lipid perturbations strongly correlate with marked microglial activation and elevated pro-inflammatory cytokine levels (IL-6, TNF-α, CCL2) in the prefrontal cortex and hippocampus. Functionally, AA supplementation alone was sufficient to recapitulate depressive-like behaviors in vivo and, through neuron-microglia co-culture assays, directly induce pro-inflammatory microglial activation, NF-κB pathway upregulation, and subsequent synaptic impairment in vitro. Critically, therapeutic intervention with aspirin, a dual COX-1/COX-2 inhibitor, effectively reversed HFD-induced behavioral deficits. This protection was mediated by a dual mechanism: directly inhibiting microglial hyperactivation and normalizing the neuroinflammatory milieu by suppressing the biosynthesis of pro-inflammatory ω-6-derived prostanoids, including AA and 12-HETE. Collectively, our findings identify AA as a critical etiological link between HFD and neuroinflammation, establishing a mechanistic framework for “metabolic depression.” The profound therapeutic efficacy of aspirin validates the AA metabolic pathway, specifically COX-1/COX-2, as a promising and targetable node for intervention, offering translational insights for the burgeoning field of nutritional psychiatry.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China",
    "Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China",
    "School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 China",
    "Department of Psychiatry, Tianjin Anding Hospital, Mental health center of Tianjin Medical University, Tianjin, 300222 China",
    "Department of Psychology and Psychiatry, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004 China",
    "Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China",
    "Shaanxi Provincial Key Laboratory of Biological Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Binbin Zhao",
      "orcid": "0000-0002-2573-4313"
    },
    {
      "affs": [
        0
      ],
      "name": "Yajuan Fan"
    },
    {
      "affs": [
        0
      ],
      "name": "Qingyan Ma"
    },
    {
      "affs": [
        2
      ],
      "name": "Jinyu Zhang"
    },
    {
      "affs": [
        3
      ],
      "name": "Xiaoying Jin"
    },
    {
      "affs": [
        4
      ],
      "name": "Yuan Peng"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenyu Xi"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiawen Wang"
    },
    {
      "affs": [
        5
      ],
      "name": "Jing Yang"
    },
    {
      "affs": [
        1
      ],
      "name": "Shan Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Mengfan Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Hua Shao"
    },
    {
      "affs": [
        0
      ],
      "name": "Min Jia",
      "orcid": "0000-0002-3213-7285"
    },
    {
      "affs": [
        0
      ],
      "name": "Binglong Wen"
    },
    {
      "affs": [
        0
      ],
      "name": "Bin Yan",
      "orcid": "0000-0001-5607-3012"
    },
    {
      "affs": [
        0
      ],
      "name": "Yijie Guo"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Wang"
    },
    {
      "affs": [
        0,
        6
      ],
      "name": "Feng Zhu",
      "orcid": "0000-0003-3986-8803"
    },
    {
      "affs": [
        0
      ],
      "name": "Yunpeng Wang",
      "orcid": "0000-0003-4291-4487"
    },
    {
      "affs": [
        1
      ],
      "name": "Yanan Wang",
      "orcid": "0000-0002-0327-0458"
    },
    {
      "affs": [
        0,
        6
      ],
      "name": "Xiancang Ma",
      "orcid": "0000-0002-7826-305X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2thpq3jjm7j4p.bib",
  "cited_by": 1,
  "doi": "10.1038/s41380-026-03752-8",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736691/",
  "id": "2thpq3jjm7j4p",
  "issns": [
    "1359-4184",
    "1476-5578"
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  "landing_url": "https://doi.org/10.1038/s41380-026-03752-8",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
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      "2803|Tryptophan and brain disorders"
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  "pdf_url": "https://www.nature.com/articles/s41380-026-03752-8.pdf",
  "pmcid": "PMC13736691",
  "pmid": "42457861",
  "published": "2026-07-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2thpq3jjm7j4p.ris",
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      "url": "https://doi.org/10.1038/s41380-026-03752-8"
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      "field": "medicine",
      "origin": "openalex:2803|Tryptophan and brain disorders",
      "subfield": "psychiatry"
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  "title": "Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation",
  "title_text": "Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:05Z",
  "url": "https://research.draconitic.com/paper/2thpq3jjm7j4p",
  "venue": "Molecular Psychiatry",
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}