{
  "abstract": "BackgroundMajor depressive disorder (MDD) is associated with impaired neural plasticity, while extracellular matrix (ECM) and perineuronal nets (PNNs) are important regulators of synaptic stability and extracellular homeostasis. However, the cellular states and molecular signatures associated with ECM/PNN alterations in MDD remain poorly understood.MethodsWe integrated bulk and single-cell transcriptomic datasets to characterize ECM/PNN-associated cellular states in MDD. Astrocyte populations were evaluated using multiple ECM/PNN scoring approaches, and disease-associated transcriptional changes were integrated with astrocyte co-expression networks to identify candidate molecular signatures. Functional enrichment, cell–cell communication, pseudotime, and in silico perturbation analyses were further used to investigate their biological context. Finally, corticosterone (CORT)-treated HT22 cells were used as a glucocorticoid-induced neuronal stress paradigm to assess stress-responsive expression of the identified genes.ResultsAmong astrocyte clusters, Cluster2 exhibited overall high ECM and PNN signature scores. Integration of Cluster2-associated co-expression modules with MDD-related differentially expressed genes identified 28 overlapping genes, from which ACSL6, FIP1L1, and ZNF709 were prioritized as cross-tissue candidate signatures showing consistent expression trends in brain and peripheral blood datasets. ACSL6 and ZNF709 were downregulated, whereas FIP1L1 was upregulated in MDD. Functional analyses implicated the three genes in metabolic and amino-acid-related processes, while FIP1L1 showed additional associations with cell adhesion, cytoskeletal organization, and synaptic signaling. Cell communication and pseudotime analyses further suggested altered intercellular signaling and increasing ECM/PNN activity across inferred astrocyte state transitions. In CORT-treated HT22 cells, ACSL6 and ZNF709 were significantly decreased, whereas FIP1L1 was increased, consistent with the transcriptomic observations.ConclusionThese findings identify an ECM/PNN-high astrocyte state and three associated cross-tissue molecular signatures in MDD. Among them, FIP1L1 emerged as a functionally prioritized candidate linked to adhesion- and synaptic-plasticity-related programs. The stress-responsive expression of these genes provides additional experimental support for their relevance to glucocorticoid-associated neuronal stress and supports an astrocyte-centered ECM/PNN working model for further mechanistic investigation.",
  "abstract_shown": true,
  "affiliations": [
    "The First Affiliated Hospital of Dali University, Dali, Yunnan, China",
    "Dali University, Dali, Yunnan, China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yifan Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yifan Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chenrui Liang"
    },
    {
      "affs": [
        1
      ],
      "name": "Chenrui Liang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiang Fu"
    },
    {
      "affs": [
        1
      ],
      "name": "Jiang Fu"
    },
    {
      "affs": [
        0
      ],
      "name": "Huating Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Huating Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiting Lei"
    },
    {
      "affs": [
        1
      ],
      "name": "Yiting Lei"
    },
    {
      "affs": [
        0
      ],
      "name": "Zijing Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Zijing Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Shuhang He"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiyan Jiang"
    },
    {
      "affs": [
        1
      ],
      "name": "Donghang Ren"
    },
    {
      "affs": [
        1
      ],
      "name": "Enqiang Dong"
    },
    {
      "affs": [
        0
      ],
      "name": "Lin Yang"
    },
    {
      "affs": [
        1
      ],
      "name": "Lin Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Lixia Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Lixia Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e09b4d47s0vt3.bib",
  "cited_by": 0,
  "doi": "10.3389/fnmol.2026.1995597",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fnmol.2026.1995597/full",
  "id": "e09b4d47s0vt3",
  "issns": [
    "1662-5099"
  ],
  "landing_url": "https://doi.org/10.3389/fnmol.2026.1995597",
  "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": [
    [
      "lcc",
      "RC321-571"
    ],
    [
      "openalex",
      "2736|Treatment of Major Depression"
    ]
  ],
  "openalex": "W7223281398",
  "pdf_url": "https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2026.1995597/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Frontiers Media S.A.",
  "ris": "https://research.draconitic.com/paper/e09b4d47s0vt3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:43:47Z",
      "native_id": "2d1bb5d43e4f44958c7e1c32b489ea23",
      "source": "doaj",
      "url": "https://doi.org/10.3389/fnmol.2026.1995597"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2736|Treatment of Major Depression",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Integrative transcriptomics reveals an ECM/PNN-high astrocyte state and cross-tissue biomarkers in major depressive disorder",
  "title_text": "Integrative transcriptomics reveals an ECM/PNN-high astrocyte state and cross-tissue biomarkers in major depressive disorder",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:47Z",
  "url": "https://research.draconitic.com/paper/e09b4d47s0vt3",
  "venue": "Frontiers in Molecular Neuroscience",
  "versions": []
}