Deciphering the molecular network of Trichostatin A in regulating Alzheimer's disease screening of core genes and mechanistic investigation based on multidimensional bioinformatics and molecular simulation.

Overview

Authors: Changze Ou^1,2, Binbin Chen^1,2, Jun Deng³, Huajun Long²

Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, China
Department of Emergency, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, Hunan, China
Department of Neurology, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine), Changsha, Hunan, China

Institutions: Hunan University of Traditional Chinese Medicine (China); Hunan Academy of Traditional Chinese Medicine (China); Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine (The Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine) (China)

Journal: PloS one, volume 21, issue 4, article e0347532

Dates: received 11 September 2025; accepted 2 April 2026; published online 20 April 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1371/journal.pone.0347532 · PMID 42008415 · PMCID PMC13094961 · OpenAlex W7155016491

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: computational modeling (no new data) (modality), human (organism), Alzheimer's / dementia (population)

Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing, Connectivity, fMRI & imaging

MeSH: Alzheimer Disease*, Computational Biology*, Gene Regulatory Networks*, Histone Deacetylase Inhibitors*, Hydroxamic Acids*, Gene Expression Regulation, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation (* major topic)

Topic: Histone Deacetylase Inhibitors Research (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: Health Commission of Hunan Province (C202303078160); Natural Science Foundation of Hunan Province (Grant No. 2026JJ81855)

Citations: not cited yet (Europe PMC); 75 references in the paper

Abstract

Background: Histone deacetylases (HDACs) regulate neuroprotection; however, Trichostatin A (TSA), an HDAC inhibitor, lacks clear molecular mechanisms and core targets in Alzheimer’s disease (AD), limiting clinical translation. This study aimed to decipher TSA’s AD-regulating network, screen core genes, and support AD early diagnosis and multi-target therapies.

Methods: TSA targets were computationally predicted. Five GEO AD datasets were analyzed for differential genes and core modules, and 130 machine learning algorithms were employed to identify core genes. Functional annotation, immune cell analysis, and single-cell expression profiling were conducted. Molecular docking and 100 ns molecular dynamics simulations verified TSA-protein interactions.

Results: 949 potential TSA targets were identified, overlapping with AD differential genes and enriching key pathways such as GABAergic synapse and tau phosphorylation. Eight machine learning-identified core genes (EFNA1, GABRB2, GABARAPL1, EGR1, CDK5, KCNC2, MET, GRIA2) exhibited a distinct AD expression pattern: synergistic downregulation of protective genes and unique upregulation of pathological EFNA1. These genes are implicated in neurotransmission, synaptic plasticity, tau clearance, and immune-neural crosstalk. Molecular dynamics simulations suggested TSA may not stably bind these candidates, implying its regulation relies on epigenetic mechanisms via HDAC1–3/6 inhibition, potentially restoring gene network balance and disrupting neuroinflammation-neurodegeneration cycles. Complex regulatory modes and cell type-specific expression were also observed.

Conclusion: This study provides preliminary insights into TSA’s putative mechanisms in AD intervention, highlighting the eight candidate core genes’ potential diagnostic and therapeutic value as AD biomarkers, supporting TSA’s multi-target therapy. All findings are computationally derived and require experimental verification.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

geo:GSE161045, at NCBI GEO; found in the text, “3.7. Single-cell data UMAP dimensionality…”

Data Availability

All relevant data are within the paper and its Supporting Information files.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 9 MeSH terms, 2 funders, 75 references.

Cite

This paper

Ou, C., Chen, B., Deng, J., & Long, H. (2026). Deciphering the molecular network of Trichostatin A in regulating Alzheimer's disease screening of core genes and mechanistic investigation based on multidimensional bioinformatics and molecular simulation. PloS one, 21(4), e0347532. https://doi.org/10.1371/journal.pone.0347532

BibTeX

@article{ou2026deciphering, author = {Ou, Changze and Chen, Binbin and Deng, Jun and Long, Huajun}, title = {{Deciphering the molecular network of Trichostatin A in regulating Alzheimer's disease screening of core genes and mechanistic investigation based on multidimensional bioinformatics and molecular simulation}}, journal = {PloS one}, year = {2026}, month = apr, volume = {21}, number = {4}, pages = {e0347532}, publisher = {PLOS}, issn = {1932-6203}, doi = {10.1371/journal.pone.0347532}, url = {https://doi.org/10.1371/journal.pone.0347532}, pmid = {42008415}, pmcid = {PMC13094961} }

RIS

TY - JOUR AU - Ou, Changze AU - Chen, Binbin AU - Deng, Jun AU - Long, Huajun TI - Deciphering the molecular network of Trichostatin A in regulating Alzheimer's disease screening of core genes and mechanistic investigation based on multidimensional bioinformatics and molecular simulation T2 - PloS one J2 - PLoS One PY - 2026 DA - 2026/04/20 VL - 21 IS - 4 SP - e0347532 SN - 1932-6203 PB - PLOS DO - 10.1371/journal.pone.0347532 UR - https://doi.org/10.1371/journal.pone.0347532 LA - en ER -

CSL-JSON

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