Discovery and validation of programmed cell death-associated key biomarker genes in ischemic stroke via ssGSEA/WGCNA and LASSO-SVM-RFE.
Overview
- Neurointerventional Center, Affiliated Hospital of Nantong University, Nantong, China
- Neurological Disease Center, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong, China
- Department of Neurosurgery, The Affiliated Kizilsu Kirghiz Autonomous Prefecture People’s Hospital of Nanjing Medical University, Artux, Xinjiang, China
Abstract
Background: Ischemic stroke (IS) currently lacks well-characterized peripheral-blood biomarkers that capture early, pathway-level biology. Programmed cell death (PCD) pathways may shape post-stroke neuroinflammation and could yield clinically informative transcriptional signatures.
Methods: Public cohorts (GSE16561 discovery; GSE58294 external test) were analyzed. We quantified sample-level pan-PCD activity using ssGSEA based on a curated PCD gene set,identified PCD-associated modules via WGCNA, and intersected with limma-derived DEGs. Two complementary machine learning (LASSO and SVM-RFE) were used to select compact candidate biomarkers. Diagnostic performance was evaluated by ROC analysis. Immune infiltration was inferred by ssGSEA (28 immune signatures) and correlated with candidate genes. Drug candidates were prioritized using Enrichr/
Results: A pan-PCD score was higher in IS than controls and guided WGCNA to a PCD-associated module. Intersection with DEGs yielded 58 PCD-related genes. LASSO and SVM-RFE converged on three biomarkers—CREBBP, ANTXR2, and ARG1. These genes showed consistent discriminative performance in both discovery (AUCs: 0.937–0.981) and external test cohorts (AUCs: 0.656–0.931) and were associated with neutrophil-skewed immune infiltration. In vivo validation in a rat MCAO model confirmed upregulation of all three genes in ischemic brain tissue. Enrichr/
Conclusion: An integrative network–ML framework delineated a peripheral-blood pan-PCD–related transcriptional pattern in IS and prioritized three biomarkers with consistent diagnostic performance and a neutrophil-skewed immune context. The exploratory pathway–gene–drug framework proposed here nominates testable compounds and provides a basis for prospective multi-cohort validation and mechanistic studies.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE16561, at NCBI GEO; found in “Data availability statement”
Other data links
- ncbi.nlm.nih.gov/
geo , NCBI; found in the text, “Data collection and preprocessing”
Data availability statement
The human transcriptomic datasets analyzed in this study are publicly available from the Gene Expression Omnibus (GEO) under accession numbers GSE16561 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Funding: added Natural Science Foundation of Jiangsu Province
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 9 authors, 6 keywords, 52 references.
Cite
This paper
Jia, Q., Zhang, P., Liu, Q., Sang, E., Chen, Z., Shao, J., Ding, Y., Bai, F., & Huang, Q. (2026). Discovery and validation of programmed cell death-associated key biomarker genes in ischemic stroke via ssGSEA/
BibTeX
@article{jia2026discover
author = {Jia, Qi and Zhang, Pengtao and Liu, Qianqian and Sang, Enze and Chen, Zhengwen and Shao, Junjie and Ding, Yuhao and Bai, Faguang and Huang, Qingfeng},
title = {{Discovery and validation of programmed cell death-associated key biomarker genes in ischemic stroke via ssGSEA/
journal = {Frontiers in molecular biosciences},
year = {2026},
month = jul,
volume = {13},
pages = {1844734},
publisher = {Frontiers Media SA},
issn = {2296-889X},
doi = {10.3389/
url = {https://
pmid = {42534680},
pmcid = {PMC13422162}
}
RIS
TY - JOUR
AU - Jia, Qi
AU - Zhang, Pengtao
AU - Liu, Qianqian
AU - Sang, Enze
AU - Chen, Zhengwen
AU - Shao, Junjie
AU - Ding, Yuhao
AU - Bai, Faguang
AU - Huang, Qingfeng
TI - Discovery and validation of programmed cell death-associated key biomarker genes in ischemic stroke via ssGSEA/
T2 - Frontiers in molecular biosciences
J2 - Front Mol Biosci
PY - 2026
DA - 2026/
VL - 13
SP - 1844734
SN - 2296-889X
PB - Frontiers Media SA
DO - 10.3389/
UR - https://
LA - en
ER -
CSL-JSON
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