Integrating ferroptosis genes and peripheral blood transcriptome to construct an early diagnostic model for stroke_West China Medical Journal

Authors：

 ZHANG Zikun , LIU Zhaoya , HE Ping

Neurological Rehabilitation Center, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, P. R. China;

Corresponding?author：

ZHANG Zikun, Email: 17551066736@163.com

Keywords：

Stroke; ferroptosis; bioinformatics; diagnostic model; transcriptome; biomarker

DOI：

10.7507/1002-0179.202601256

Video：

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Objective To use peripheral blood transcriptome data to identify stroke-related ferroptosis key genes and establish an early diagnostic model. Methods The GSE58294 dataset from the Gene Expression Omnibus database was used as the training set, and the GSE202518 dataset was used for validation. Differentially expressed genes (DEGs) were identified and intersected with the ferroptosis-related gene set from FerrDb to obtain key genes. Functional enrichment analysis was performed using gene ontology and Kyoto Encyclopedia of Genes and Genomes. A risk prediction model was built using the Ridge regression algorithm and evaluated via cross-validation and independent validation. Results A total of 649 significant DEGs were identified. Intersection with the ferroptosis gene set yielded five key genes: MAPK1, SP1, MAPK14, STAT3, and PTGS2. Functional enrichment analysis revealed their significant involvement in core stroke pathways, including inflammatory response regulation and the MAPK signaling pathway. The Ridge regression model based on these five genes achieved an area under the curve of 0.968 in the training set and 0.854 in the independent validation set. Conclusion The five-gene diagnostic model demonstrated robust performance, laying the groundwork for non-invasive early stroke diagnosis.

Citation： ZHANG Zikun, LIU Zhaoya, HE Ping. Integrating ferroptosis genes and peripheral blood transcriptome to construct an early diagnostic model for stroke. West China Medical Journal, 2026, 41(7): 1129-1134. doi: 10.7507/1002-0179.202601256 Copy

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14.	Ma S, Zhang X, Fan J, et al. DUSP1-mediated suppression of p38 MAPK signaling pathway reduces ferroptosis in cerebral ischemia-reperfusion injury[J]. Neurochem Int, 2025, 189: 106024.
15.	Sun Y, Liu WZ, Liu T, et al. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis[J]. J Recept Signal Transduct, 2015, 35(6): 600-604.
16.	徐濤, 井文君, 陳貴蘭. 線粒體內膜蛋白 17(MPV17)通過阻斷 ERK 通路抑制鐵過載小鼠脾臟 CD3+T 細胞鐵死亡[J]. 細胞與分子免疫學雜志, 2024, 40(5): 395-403.
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1. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019[J]. Lancet Neurol, 2021, 20(10): 973-1003.
2. Naik A, Adeleye O, Koester SW, et al. Cerebrospinal fluid biomarkers for diagnosis and the prognostication of acute ischemic stroke: a systematic review[J]. Int J Mol Sci, 2023, 24(13): 10902.
3. Liu C, Wang G, Han W, et al. Ferroptosis: a potential therapeutic target for stroke[J]. Neural Regen Res, 2024, 19(5): 988-997.
4. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell, 2017, 171(2): 273-285.
5. Carmona-Mora P, Ander BP, Jickling GC, et al. Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke[J]. J Cereb Blood Flow Metab, 2021, 41(6): 1398-1416.
6. Montellano FA, Ungethüm K, Ramiro L, et al. Role of blood-based biomarkers in ischemic stroke prognosis: a systematic review[J]. Stroke, 2021, 52(2): 543-551.
7. Labarga A, Martínez-Gonzalez J, Barajas M. Integrative multi-omics analysis for etiology classification and biomarker discovery in stroke: advancing towards precision medicine[J]. Biology, 2024, 13(5): 338.
8. Qu R, Zhang Y, Zhang H, et al. Exploring ischemic stroke based on the ferroptosis perspective: ECH1 may serve as a new biomarker and therapeutic target[J]. Front Neurosci, 2025, 19: 1622760.
9. Szczepanski A, Tsuboyama N, Lyu H, et al. A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer[J]. Nat Commun, 2024, 15: 2067.
10. Han Y, Wu J, Gong Z, et al. Identification and development of a novel 5-gene diagnostic model based on immune infiltration analysis of osteoarthritis[J]. J Transl Med, 2021, 19: 522.
11. Carmona-Mora P, Knepp B, Jickling GC, et al. Monocyte, neutrophil, and whole blood transcriptome dynamics following ischemic stroke[J]. BMC Med, 2023, 21: 65.
12. Long Z, Zhu Y, Zhao H, et al. Ferroptosis in ischemic stroke: mechanisms, pathological implications, and therapeutic strategies[J]. Front Neurosci, 2025, 19: 1623485.
13. Zou Z, Zhang Y, Guo C, et al. ARIP1 deficiency facilitates the inhibition of neuronal ferroptosis in cerebral ischemia by activin A through SMAD3 and p38 MAPK signaling[J]. CNS Neurosci Ther, 2025, 31(9): e70615.
14. Ma S, Zhang X, Fan J, et al. DUSP1-mediated suppression of p38 MAPK signaling pathway reduces ferroptosis in cerebral ischemia-reperfusion injury[J]. Neurochem Int, 2025, 189: 106024.
15. Sun Y, Liu WZ, Liu T, et al. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis[J]. J Recept Signal Transduct, 2015, 35(6): 600-604.
16. 徐濤, 井文君, 陳貴蘭. 線粒體內膜蛋白 17(MPV17)通過阻斷 ERK 通路抑制鐵過載小鼠脾臟 CD3+T 細胞鐵死亡[J]. 細胞與分子免疫學雜志, 2024, 40(5): 395-403.
17. Dai Y, Cui C, Jiao D, et al. JAK/STAT signaling as a key regulator of ferroptosis: mechanisms and therapeutic potentials in cancer and diseases[J]. Cancer Cell Int, 2025, 25(1): 83.
18. Hu X, Bao Y, Li M, et al. The role of ferroptosis and its mechanism in ischemic stroke[J]. Exp Neurol, 2024, 372: 114630.
19. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation[J]. Trends Cell Biol. 2016, 26(3): 165-176.
20. Yi L, Hu Y, Wu Z, et al. TFRC upregulation promotes ferroptosis in CVB3 infection via nucleus recruitment of Sp1[J]. Cell Death Dis, 2022, 13(7): 592.

West China Medical Journal

Integrating ferroptosis genes and peripheral blood transcriptome to construct an early diagnostic model for stroke

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