Xinyu Yang, Qiaochu Li, Linbang Wang, Jiaxing Chen, Zhengxue Quan
{"title":"通过综合生物信息学和实验验证 MUC1 和 CREB3 是核浆和纤维环变性的枢纽铁突变抑制因子","authors":"Xinyu Yang, Qiaochu Li, Linbang Wang, Jiaxing Chen, Zhengxue Quan","doi":"10.2147/JIR.S489052","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Ferroptosis is an underlying mechanism for various degenerative diseases, but its role in intervertebral disc degeneration remains elusive. This study aims to explore the key ferroptosis-related genes and its role in nucleus pulposus (NP) and annulus fibrosus (AF) degeneration.</p><p><strong>Methods: </strong>We analyzed the gene expression profiles of NP and AF from the Gene Expression Omnibus database. The ferroptosis-related differentially expressed genes (FRDEGs) in degenerated NP and AF were filtered, followed by GO and KEGG analysis. Feature FRDEGs were identified by the LASSO and SVM-RFE algorithms, and then Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted. Immune infiltration analysis was conducted by CIBERSORT algorithm. We established drug networks via the Drug-Gene Interaction Database and competitive endogenous RNA (ceRNA) networks via miRanda, miRDB, and TargetScan database. The expression levels of the feature FRDEGs were assessed by the validation sets, single-cell RNA-seq, and experimental verification.</p><p><strong>Results: </strong>A total of 15 and 18 FRDEGs were obtained for NP and AF, respectively. GO and KEGG analysis revealed their implication in oxidative stress. Four (AKR1C1, AKR1C3, MUC1, ENPP2) and five (SCP2, ABCC1, KLF2, IDO1, CREB3) feature genes were identified for NP and AF, respectively. The GSEA and GSVA analysis showed that these feature genes were enriched in lots of biological functions, including immune response. CREB3 in degenerated AF was negatively correlated with Eosinophils via CIBERSORT algorithm. The drugs and ceRNAs targeting CREB3 and MUC1 were identified. Experimental verification and single-cell RNA-seq analysis revealed that MUC1 and CREB3 were downregulated in degenerated NP and AF, respectively.</p><p><strong>Conclusion: </strong>MUC1 and CREB3 were considered novel biomarkers for NP and AF ferroptosis, respectively. Drug and ceRNA networks were constructed for future drug development and investigation of new mechanisms of ferroptosis.</p>","PeriodicalId":16107,"journal":{"name":"Journal of Inflammation Research","volume":"17 ","pages":"8965-8984"},"PeriodicalIF":4.2000,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584408/pdf/","citationCount":"0","resultStr":"{\"title\":\"MUC1 and CREB3 are Hub Ferroptosis Suppressors for Nucleus Pulposus and Annulus Fibrosus Degeneration by Integrated Bioinformatics and Experimental Verification.\",\"authors\":\"Xinyu Yang, Qiaochu Li, Linbang Wang, Jiaxing Chen, Zhengxue Quan\",\"doi\":\"10.2147/JIR.S489052\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Ferroptosis is an underlying mechanism for various degenerative diseases, but its role in intervertebral disc degeneration remains elusive. This study aims to explore the key ferroptosis-related genes and its role in nucleus pulposus (NP) and annulus fibrosus (AF) degeneration.</p><p><strong>Methods: </strong>We analyzed the gene expression profiles of NP and AF from the Gene Expression Omnibus database. The ferroptosis-related differentially expressed genes (FRDEGs) in degenerated NP and AF were filtered, followed by GO and KEGG analysis. Feature FRDEGs were identified by the LASSO and SVM-RFE algorithms, and then Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted. Immune infiltration analysis was conducted by CIBERSORT algorithm. We established drug networks via the Drug-Gene Interaction Database and competitive endogenous RNA (ceRNA) networks via miRanda, miRDB, and TargetScan database. The expression levels of the feature FRDEGs were assessed by the validation sets, single-cell RNA-seq, and experimental verification.</p><p><strong>Results: </strong>A total of 15 and 18 FRDEGs were obtained for NP and AF, respectively. GO and KEGG analysis revealed their implication in oxidative stress. Four (AKR1C1, AKR1C3, MUC1, ENPP2) and five (SCP2, ABCC1, KLF2, IDO1, CREB3) feature genes were identified for NP and AF, respectively. The GSEA and GSVA analysis showed that these feature genes were enriched in lots of biological functions, including immune response. CREB3 in degenerated AF was negatively correlated with Eosinophils via CIBERSORT algorithm. The drugs and ceRNAs targeting CREB3 and MUC1 were identified. Experimental verification and single-cell RNA-seq analysis revealed that MUC1 and CREB3 were downregulated in degenerated NP and AF, respectively.</p><p><strong>Conclusion: </strong>MUC1 and CREB3 were considered novel biomarkers for NP and AF ferroptosis, respectively. 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引用次数: 0
摘要
目的：铁蜕变是多种退行性疾病的潜在机制之一，但其在椎间盘退变中的作用仍不明确。本研究旨在探究髓核（NP）和纤维环（AF）退变中与铁噬相关的关键基因及其作用：我们分析了基因表达总库（Gene Expression Omnibus）数据库中NP和AF的基因表达谱。筛选出变性 NP 和 AF 中与铁突变相关的差异表达基因（FRDEGs），然后进行 GO 和 KEGG 分析。利用 LASSO 和 SVM-RFE 算法识别特征 FRDEGs，然后进行基因组富集分析（GSEA）和基因组变异分析（GSVA）。免疫浸润分析是通过 CIBERSORT 算法进行的。我们通过药物-基因相互作用数据库建立了药物网络，通过miRanda、miRDB和TargetScan数据库建立了竞争性内源性RNA（ceRNA）网络。通过验证集、单细胞RNA-seq和实验验证评估了特征FRDEGs的表达水平：结果：NP和AF分别获得了15个和18个FRDEGs。GO和KEGG分析显示它们与氧化应激有关。NP和AF的特征基因分别为4个（AKR1C1、AKR1C3、MUC1、ENPP2）和5个（SCP2、ABCC1、KLF2、IDO1、CREB3）。GSEA和GSVA分析表明，这些特征基因富集于多种生物学功能，包括免疫反应。通过 CIBERSORT 算法，变性 AF 中的 CREB3 与嗜酸性粒细胞呈负相关。鉴定了靶向 CREB3 和 MUC1 的药物和 ceRNA。实验验证和单细胞RNA-seq分析表明，MUC1和CREB3分别在变性NP和AF中下调：结论：MUC1和CREB3分别被认为是NP和AF铁变态反应的新型生物标记物。结论：MUC1和CREB3分别被认为是NP和AF铁变态反应的新型生物标记物，药物和ceRNA网络的构建有助于未来的药物开发和铁变态反应新机制的研究。
MUC1 and CREB3 are Hub Ferroptosis Suppressors for Nucleus Pulposus and Annulus Fibrosus Degeneration by Integrated Bioinformatics and Experimental Verification.
Purpose: Ferroptosis is an underlying mechanism for various degenerative diseases, but its role in intervertebral disc degeneration remains elusive. This study aims to explore the key ferroptosis-related genes and its role in nucleus pulposus (NP) and annulus fibrosus (AF) degeneration.
Methods: We analyzed the gene expression profiles of NP and AF from the Gene Expression Omnibus database. The ferroptosis-related differentially expressed genes (FRDEGs) in degenerated NP and AF were filtered, followed by GO and KEGG analysis. Feature FRDEGs were identified by the LASSO and SVM-RFE algorithms, and then Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted. Immune infiltration analysis was conducted by CIBERSORT algorithm. We established drug networks via the Drug-Gene Interaction Database and competitive endogenous RNA (ceRNA) networks via miRanda, miRDB, and TargetScan database. The expression levels of the feature FRDEGs were assessed by the validation sets, single-cell RNA-seq, and experimental verification.
Results: A total of 15 and 18 FRDEGs were obtained for NP and AF, respectively. GO and KEGG analysis revealed their implication in oxidative stress. Four (AKR1C1, AKR1C3, MUC1, ENPP2) and five (SCP2, ABCC1, KLF2, IDO1, CREB3) feature genes were identified for NP and AF, respectively. The GSEA and GSVA analysis showed that these feature genes were enriched in lots of biological functions, including immune response. CREB3 in degenerated AF was negatively correlated with Eosinophils via CIBERSORT algorithm. The drugs and ceRNAs targeting CREB3 and MUC1 were identified. Experimental verification and single-cell RNA-seq analysis revealed that MUC1 and CREB3 were downregulated in degenerated NP and AF, respectively.
Conclusion: MUC1 and CREB3 were considered novel biomarkers for NP and AF ferroptosis, respectively. Drug and ceRNA networks were constructed for future drug development and investigation of new mechanisms of ferroptosis.
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An international, peer-reviewed, open access, online journal that welcomes laboratory and clinical findings on the molecular basis, cell biology and pharmacology of inflammation.
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