{"title":"关键铜稳态基因和缺血性卒中炎症机制：生物信息学和实验研究","authors":"Ting Shi, Zhifeng Wang, Jiao Yang, Pengfen He, Daman Tian, Junfeng Lan, Shuangfeng Xu, Aiming Yang, Liwei Xing, Yujiang Xi, Jian Wang","doi":"10.1007/s10142-025-01692-0","DOIUrl":null,"url":null,"abstract":"<div><p>Ischemic stroke (IS) has high morbidity/mortality with limited treatments. This study screened core copper homeostasis-related genes in IS and validated their function as precise intervention targets. Human IS gene chip data were retrieved from GEO, and copper homeostasis genes from multiple databases. After data correction/normalization, IS differentially expressed genes (DEGs) were identified and intersected with copper genes. DAVID for GO/KEGG enrichment, STRING for PPI network, CytoHubba for key genes, and ROC curves for diagnostic value. MCAO rat models were established; after 14-day rearing, protein expression was validated via relevant assays. 1,425 IS DEGs and 2,610 copper genes intersected to 235 genes, enriched in inflammatory response, innate immunity, and TNF/NOD-like/Toll-like receptor pathways. Key genes HIF-1α, TNF, TLR4, IL-1β had IS diagnostic AUC 0.70–0.80. MCAO rats showed worse neurological deficits, larger infarcts, neuronal damage, brain copper accumulation, and upregulated key genes linked to neuroinflammation, BBB disruption, and neuronal injury. Bioinformatics and animal studies revealed copper homeostasis imbalance-related genes mediate inflammation, oxidative stress, and mitochondrial regulation, supporting the \"copper accumulation–inflammation–oxidative stress\" cascade. These genes may be novel IS targets. Further study on dynamic expression across ischemic time windows/brain regions and interactions with other cell death modes is needed.</p><h3>Graphical abstract</h3><p>This study used a system approach: bioinformatics screening → experimental validation → mechanism elucidation. Three cerebral ischemia datasets from GEO (GSE16561, GSE22255, GSE58294) underwent DEG analysis; Venn diagram identified core shared DEGs. GO/KEGG enrichment, STRING for PPI network, Cytoscape for hub genes, ROC curves for diagnostic potential. Rat MCAO model was established; validity verified via relevant staining; Cu2+ accumulation detected; molecular expression validated by assays.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Key copper homeostasis genes and inflammatory mechanisms in ischemic stroke: A bioinformatics and experimental study\",\"authors\":\"Ting Shi, Zhifeng Wang, Jiao Yang, Pengfen He, Daman Tian, Junfeng Lan, Shuangfeng Xu, Aiming Yang, Liwei Xing, Yujiang Xi, Jian Wang\",\"doi\":\"10.1007/s10142-025-01692-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Ischemic stroke (IS) has high morbidity/mortality with limited treatments. This study screened core copper homeostasis-related genes in IS and validated their function as precise intervention targets. Human IS gene chip data were retrieved from GEO, and copper homeostasis genes from multiple databases. After data correction/normalization, IS differentially expressed genes (DEGs) were identified and intersected with copper genes. DAVID for GO/KEGG enrichment, STRING for PPI network, CytoHubba for key genes, and ROC curves for diagnostic value. MCAO rat models were established; after 14-day rearing, protein expression was validated via relevant assays. 1,425 IS DEGs and 2,610 copper genes intersected to 235 genes, enriched in inflammatory response, innate immunity, and TNF/NOD-like/Toll-like receptor pathways. Key genes HIF-1α, TNF, TLR4, IL-1β had IS diagnostic AUC 0.70–0.80. MCAO rats showed worse neurological deficits, larger infarcts, neuronal damage, brain copper accumulation, and upregulated key genes linked to neuroinflammation, BBB disruption, and neuronal injury. Bioinformatics and animal studies revealed copper homeostasis imbalance-related genes mediate inflammation, oxidative stress, and mitochondrial regulation, supporting the \\\"copper accumulation–inflammation–oxidative stress\\\" cascade. These genes may be novel IS targets. Further study on dynamic expression across ischemic time windows/brain regions and interactions with other cell death modes is needed.</p><h3>Graphical abstract</h3><p>This study used a system approach: bioinformatics screening → experimental validation → mechanism elucidation. Three cerebral ischemia datasets from GEO (GSE16561, GSE22255, GSE58294) underwent DEG analysis; Venn diagram identified core shared DEGs. GO/KEGG enrichment, STRING for PPI network, Cytoscape for hub genes, ROC curves for diagnostic potential. Rat MCAO model was established; validity verified via relevant staining; Cu2+ accumulation detected; molecular expression validated by assays.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>\",\"PeriodicalId\":574,\"journal\":{\"name\":\"Functional & Integrative Genomics\",\"volume\":\"25 1\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Functional & Integrative Genomics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10142-025-01692-0\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Functional & Integrative Genomics","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10142-025-01692-0","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Key copper homeostasis genes and inflammatory mechanisms in ischemic stroke: A bioinformatics and experimental study
Ischemic stroke (IS) has high morbidity/mortality with limited treatments. This study screened core copper homeostasis-related genes in IS and validated their function as precise intervention targets. Human IS gene chip data were retrieved from GEO, and copper homeostasis genes from multiple databases. After data correction/normalization, IS differentially expressed genes (DEGs) were identified and intersected with copper genes. DAVID for GO/KEGG enrichment, STRING for PPI network, CytoHubba for key genes, and ROC curves for diagnostic value. MCAO rat models were established; after 14-day rearing, protein expression was validated via relevant assays. 1,425 IS DEGs and 2,610 copper genes intersected to 235 genes, enriched in inflammatory response, innate immunity, and TNF/NOD-like/Toll-like receptor pathways. Key genes HIF-1α, TNF, TLR4, IL-1β had IS diagnostic AUC 0.70–0.80. MCAO rats showed worse neurological deficits, larger infarcts, neuronal damage, brain copper accumulation, and upregulated key genes linked to neuroinflammation, BBB disruption, and neuronal injury. Bioinformatics and animal studies revealed copper homeostasis imbalance-related genes mediate inflammation, oxidative stress, and mitochondrial regulation, supporting the "copper accumulation–inflammation–oxidative stress" cascade. These genes may be novel IS targets. Further study on dynamic expression across ischemic time windows/brain regions and interactions with other cell death modes is needed.
Graphical abstract
This study used a system approach: bioinformatics screening → experimental validation → mechanism elucidation. Three cerebral ischemia datasets from GEO (GSE16561, GSE22255, GSE58294) underwent DEG analysis; Venn diagram identified core shared DEGs. GO/KEGG enrichment, STRING for PPI network, Cytoscape for hub genes, ROC curves for diagnostic potential. Rat MCAO model was established; validity verified via relevant staining; Cu2+ accumulation detected; molecular expression validated by assays.
期刊介绍：
Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?
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