Integrative transcriptomics reveals an ECM/PNN-high astrocyte state and cross-tissue biomarkers in major depressive disorder
- 1The First Affiliated Hospital of Dali University, Dali, Yunnan, China
- 2Dali University, Dali, Yunnan, China
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.
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BibTeX
@article{wang2026integrative,
title = {{Integrative transcriptomics reveals an ECM/PNN-high astrocyte state and cross-tissue biomarkers in major depressive disorder}},
author = {Yifan Wang and Yifan Wang and Chenrui Liang and Chenrui Liang and Jiang Fu and Jiang Fu and Huating Liu and Huating Liu and Yiting Lei and Yiting Lei and Zijing Liu and Zijing Liu and Shuhang He and Xiyan Jiang and Donghang Ren and Enqiang Dong and Lin Yang and Lin Yang and Lixia Wang and Lixia Wang},
journal = {Frontiers in Molecular Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnmol.2026.1995597},
url = {https://doi.org/10.3389/fnmol.2026.1995597},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integrative transcriptomics reveals an ECM/PNN-high astrocyte state and cross-tissue biomarkers in major depressive disorder
AU - Yifan Wang
AU - Yifan Wang
AU - Chenrui Liang
AU - Chenrui Liang
AU - Jiang Fu
AU - Jiang Fu
AU - Huating Liu
AU - Huating Liu
AU - Yiting Lei
AU - Yiting Lei
AU - Zijing Liu
AU - Zijing Liu
AU - Shuhang He
AU - Xiyan Jiang
AU - Donghang Ren
AU - Enqiang Dong
AU - Lin Yang
AU - Lin Yang
AU - Lixia Wang
AU - Lixia Wang
PY - 2026
DA - 2026/10/23
JO - Frontiers in Molecular Neuroscience
DO - 10.3389/fnmol.2026.1995597
UR - https://doi.org/10.3389/fnmol.2026.1995597
AB - 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.
SN - 1662-5099
ER -