Scholarlink

Background <p>Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its severe cardiotoxicity limits its clinical application. Many biological processes and molecular mechanisms have been implicated in DOX-induced cardiotoxicity. However, the mechanisms underlying DOX-induced cardiotoxicity remain largely unknown. This study aimed to identify key regulatory genes and select targeted drugs for DOX-induced cardiotoxicity.</p> Methods <p>RNA-seq analysis was used to identify differentially expressed genes (DEGs) in DOX-treated cardiomyocytes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to elucidate the biological significance of the DEGs. Protein-protein interaction (PPI) network and maximum clique centrality (MCC) algorithm in Cytoscape software were used to identify central regulatory genes. Gene Set Enrichment Analysis (GSEA) was used to verify the key gene involved in DOX-induced cardiotoxicity. Molecular docking analysis was used to identify the inhibitors of the key gene. Cell Counting Kit-8 (CCK-8) assay, Western blot, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) detection kits, and Hematoxylin and Eosin (HE) staining were used to investigate the protective effect of SB-431,542 against DOX-induced cardiomyocyte injury.</p> Results <p>RNA-seq analysis revealed significant transcriptional changes. Upregulated genes wereassociated with oxidative stress and apoptosis, while downregulated genes were linked to disrupted signaling pathways. Differential expression analysis identified interleukin-6 (Il6), transforming growth factor-beta 1 (TGF-β1), intercellular adhesion molecule-1 (Icam1), serine peptidase inhibitor clade E member 1 (Serpine1), and angiotensinogen (Agt) as central regulators of DOX-induced cellular responses. Functional enrichment analysis highlighted the involvement of mitogen-activated protein kinase (MAPK), receptor for advanced glycation endproducts (RAGE), and TGF-β signaling pathways. Further analysis identified TGF-β1 as a key regulatory hub connecting the MAPK pathway and protein-protein interaction networks. GSEA confirmed TGF-β pathway enrichment, emphasizing its role in inflammation, fibrosis, and oxidative stress. Notably, SB-431,542, a TGF-β receptor kinase inhibitor, mitigated DOX-induced apoptosis, improved cell viability, and ameliorated DOX-induced cardiotoxicity by inhibiting the phosphorylation of Smad2/3.</p> Conclusion <p>Our study identifies TGF-β1 as a central regulator of DOX-induced cardiotoxicity and highlights SB-431,542 as a promising therapeutic agent for mitigating cardiomyocyte apoptosis by targeting Smad2/3. Our study suggests that TGF-β1 may serve as a potential therapeutic target for reducing DOX-induced cardiotoxicity.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Identification of TGF-β1 as a key regulator in DOX-induced cardiotoxicity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月14日

查看全文
  • Cong Mao,
  • Zhuo Zhang,
  • Dabao Xiao,
  • Junru He,
  • Xu Leng,
  • Wenzhen Zhao,
  • Mengya Zeng,
  • Keyan Zhong,
  • Yuewu Chen

摘要

Background

Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its severe cardiotoxicity limits its clinical application. Many biological processes and molecular mechanisms have been implicated in DOX-induced cardiotoxicity. However, the mechanisms underlying DOX-induced cardiotoxicity remain largely unknown. This study aimed to identify key regulatory genes and select targeted drugs for DOX-induced cardiotoxicity.

Methods

RNA-seq analysis was used to identify differentially expressed genes (DEGs) in DOX-treated cardiomyocytes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to elucidate the biological significance of the DEGs. Protein-protein interaction (PPI) network and maximum clique centrality (MCC) algorithm in Cytoscape software were used to identify central regulatory genes. Gene Set Enrichment Analysis (GSEA) was used to verify the key gene involved in DOX-induced cardiotoxicity. Molecular docking analysis was used to identify the inhibitors of the key gene. Cell Counting Kit-8 (CCK-8) assay, Western blot, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) detection kits, and Hematoxylin and Eosin (HE) staining were used to investigate the protective effect of SB-431,542 against DOX-induced cardiomyocyte injury.

Results

RNA-seq analysis revealed significant transcriptional changes. Upregulated genes wereassociated with oxidative stress and apoptosis, while downregulated genes were linked to disrupted signaling pathways. Differential expression analysis identified interleukin-6 (Il6), transforming growth factor-beta 1 (TGF-β1), intercellular adhesion molecule-1 (Icam1), serine peptidase inhibitor clade E member 1 (Serpine1), and angiotensinogen (Agt) as central regulators of DOX-induced cellular responses. Functional enrichment analysis highlighted the involvement of mitogen-activated protein kinase (MAPK), receptor for advanced glycation endproducts (RAGE), and TGF-β signaling pathways. Further analysis identified TGF-β1 as a key regulatory hub connecting the MAPK pathway and protein-protein interaction networks. GSEA confirmed TGF-β pathway enrichment, emphasizing its role in inflammation, fibrosis, and oxidative stress. Notably, SB-431,542, a TGF-β receptor kinase inhibitor, mitigated DOX-induced apoptosis, improved cell viability, and ameliorated DOX-induced cardiotoxicity by inhibiting the phosphorylation of Smad2/3.

Conclusion

Our study identifies TGF-β1 as a central regulator of DOX-induced cardiotoxicity and highlights SB-431,542 as a promising therapeutic agent for mitigating cardiomyocyte apoptosis by targeting Smad2/3. Our study suggests that TGF-β1 may serve as a potential therapeutic target for reducing DOX-induced cardiotoxicity.