Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation
7 affiliations
- 1Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
- 2Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
- 3School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617 China
- 4Department of Psychiatry, Tianjin Anding Hospital, Mental health center of Tianjin Medical University, Tianjin, 300222 China
- 5Department of Psychology and Psychiatry, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004 China
- 6Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
- 7Shaanxi Provincial Key Laboratory of Biological Psychiatry, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
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.
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BibTeX
@article{zhao2026aspirin,
title = {{Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation}},
author = {Binbin Zhao and Yajuan Fan and Qingyan Ma and Jinyu Zhang and Xiaoying Jin and Yuan Peng and Wenyu Xi and Jiawen Wang and Jing Yang and Shan Wang and Mengfan Zhang and Hua Shao and Min Jia and Binglong Wen and Bin Yan and Yijie Guo and Wei Wang and Feng Zhu and Yunpeng Wang and Yanan Wang and Xiancang Ma},
journal = {Molecular Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41380-026-03752-8},
url = {https://doi.org/10.1038/s41380-026-03752-8},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Aspirin alleviates long-term high-fat diet-induced depressive-like behavior in male mice via suppressing arachidonic acid-mediated microglial activation and neuroinflammation
AU - Binbin Zhao
AU - Yajuan Fan
AU - Qingyan Ma
AU - Jinyu Zhang
AU - Xiaoying Jin
AU - Yuan Peng
AU - Wenyu Xi
AU - Jiawen Wang
AU - Jing Yang
AU - Shan Wang
AU - Mengfan Zhang
AU - Hua Shao
AU - Min Jia
AU - Binglong Wen
AU - Bin Yan
AU - Yijie Guo
AU - Wei Wang
AU - Feng Zhu
AU - Yunpeng Wang
AU - Yanan Wang
AU - Xiancang Ma
PY - 2026
DA - 2026/07/15
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03752-8
UR - https://doi.org/10.1038/s41380-026-03752-8
AB - 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.
SN - 1359-4184
SN - 1476-5578
ER -