Comparative Analysis of Ferroptosis- and Mitochondria-Related Genes in Ischemic Stroke via Bioinformatics Analysis and Experimental Validation.

Overview

1. College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China
2. The Affiliated Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, People’s Republic of China
3. Fujian Key Laboratory of Rehabilitation Technology, Fuzhou, People’s Republic of China

Abstract

Background: Ischemic stroke (IS) is a major cause of death and long-term disability worldwide. Multiple complex biological processes contribute to IS-related neuronal death, among which oxidative stress plays a central role in disease progression. Increasing evidence suggests that oxidative stress–induced neuronal injury is closely associated with ferroptosis and mitochondrial dysfunction, both of which contribute to excessive reactive oxygen species accumulation, lipid peroxidation, and impaired cellular energy metabolism during cerebral ischemia. However, their relative contributions and associated molecular signatures in IS have not been systematically compared. Therefore, this study aimed to identify ferroptosis- and mitochondria-associated genes involved in oxidative stress and neuronal injury in IS and to explore their potential as therapeutic targets for ischemic brain injury.

Methods: Two public microarray datasets (GSE22255 and GSE58294) were integrated and analyzed using weighted gene co-expression network analysis (WGCNA) to identify IS-associated gene modules. Ferroptosis-related genes from FerrDb and mitochondria-associated genes from MitoCarta3.0 were intersected with key modules to screen candidate genes. Protein–protein interaction analysis and CytoHubba were applied to identify hub genes. Logistic regression models were constructed to compare the diagnostic performance of ferroptosis- and mitochondria-related gene signatures. Functional enrichment analyses were conducted using Gene Ontology and KEGG. Key genes were further validated in a rat middle cerebral artery occlusion/reperfusion (MCAO/R) model treated with the ferroptosis inhibitor Ferrostatin-1 (Fer-1).

Results: Nine ferroptosis-related hub genes and nine mitochondria-related hub genes were identified. The ferroptosis-based diagnostic model showed significantly higher discriminatory power than the mitochondrial model (AUC = 0.949 vs. 0.829). Among these genes, GSK3B, IDH1, and PRDX1 exhibited the most prominent differential expression and were selected as core genes. In vivo experiments demonstrated that Fer-1 markedly reduced infarct volume, improved neurological function, attenuated oxidative stress, and restored the ACSL4/GPX4/TFR1 signaling axis. Fer-1 also reversed MCAO-induced dysregulation of GSK3B phosphorylation, IDH1, and PRDX1 expression, indicating effective suppression of ferroptosis.

Conclusion: Ferroptosis-related gene signatures outperform mitochondria-associated genes in the diagnosis of ischemic stroke. GSK3B, IDH1, and PRDX1 represent key molecular regulators linking oxidative stress to ferroptotic neuronal injury and may serve as promising biomarkers and therapeutic targets for ischemic stroke.

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

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Data

Datasets cited

• geo:GSE22255 — at NCBI GEO; found in the text, “Data Preparation and Processing”

Other data links

• ncbi.nlm.nih.gov/geo — NCBI; found in the text, “Data Preparation and Processing”

Data Sharing Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

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

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Version 2, 28 September 2026

• Funding: added National Natural Science Foundation of China; Fujian Provincial Health Commission

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 9 authors, 7 keywords, 34 references.

Cite

This paper

Ma, K., Jiang, Y., Yang, Y., Rao, T., Zhan, Y., Yin, Z., Dan, Y., Xu, S., & Yang, S. (2026). Comparative Analysis of Ferroptosis- and Mitochondria-Related Genes in Ischemic Stroke via Bioinformatics Analysis and Experimental Validation. Journal of inflammation research, 19, 605715. https://doi.org/10.2147/jir.s605715

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