Evidence map›Paper›PMID 40643722›Full record

ArticleMetabolomics : Official journal of the Metabolomic Society2025

Metabolite classification through novel metabolomics framework reveals mechanism underlying the therapeutic effects of PSD95-nNOS blockade for post-stroke depression.

Yudie Hu, Ran Xiao, Cong Wang, Huihui Meng, Benxing Yao, Qian Xu, Xi Xu, Junsong Wang

Abstract read
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In one paragraph

Article in Metabolomics : Official journal of the Metabolomic Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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0cells of the map it votes in
1citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

8 authors.

Yudie HuCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Ran XiaoCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Cong WangCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Huihui MengCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Benxing YaoCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Qian XuCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Xi XuCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China. xuxi@njust.edu.cn.
Junsong WangCenter of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China. wangjunsong@njust.edu.cn.

Funding

Fundamental Research Funds for the Central Universities Grant No. 2025101001National Natural Science Foundation of China Grant No. 81773857
6 · The paper itself

Abstract

introductionPost-stroke depression (PSD) pathophysiology involves glutamate excitotoxicity mediated through 'postsynaptic density protein95-neuronal nitric oxide synthase' (PSD95-nNOS) coupling. However, the therapeutic mechanisms of targeting this complex remain incompletely understood.

objectiveTo elucidate the antidepressant mechanisms of the PSD95-nNOS decoupler ZL006 using an innovative integrated metabolomics approach.

methodsWe developed an innovative integrated metabolomics approach to investigate the antidepressant mechanisms of ZL006, a selective PSD95-nNOS decoupler. Using a rat model of PSD, we employed untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics combined with a novel analytical framework that distinguished treatment efficacy-associated metabolites from drug bias-associated ones. This classification enabled identification of primary drug mechanisms versus secondary responses. Pathway analyses focused on proteins interacting with drug-specific metabolites, with key findings validated through quantitative polymerase chain reaction (qPCR).

resultsZL006 demonstrated dose-dependent antidepressant effects while modulating multiple neurotransmitter pathways, including tryptophan, tyrosine, and arginine metabolism, along with steroid hormone synthesis. Our integrated metabolomics approach revealed vascular endothelial growth factor (VEGF) signaling, hypoxia-inducible factor (HIF) pathway, and tight junction regulation as primary mechanisms of action.

conclusionThis novel metabolomics strategy, by discriminating between treatment-associated and compound-intrinsic pathways, provided unprecedented mechanistic insights into ZL006's therapeutic effects. The findings suggest that ZL006 alleviates PSD through coordinated modulation of neuroplasticity, angiogenesis, and stress responses via PSD95-nNOS targeting. This integrated analytical approach presents a valuable framework for mechanistic investigation of therapeutic compounds.

Indexed as

Antidepressive AgentsDepressionDisks Large Homolog 4 ProteinMetabolomicsNitric Oxide Synthase Type IStrokeAnimalsChromatography, LiquidDisease Models, AnimalMaleMetabolomeRatsRats, Sprague-DawleyAntidepressive AgentsDisks Large Homolog 4 ProteinDlg4 protein, ratNitric Oxide Synthase Type IMetabolomicsPathway analysisPost-stroke depressionPSD95-nNOSZL006

Identifiers

PMID40643722

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.