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<p>Colorectal cancer (CRC) is a prevalent type of cancer affecting the digestive system, characterized by a complex and not fully understood development process. Inflammation and metabolic processes are thought to play significant roles in both the initiation and progression of this disease. This study aimed to clarify the causal relationships between CRC and specific inflammatory proteins, immune cell types, and metabolites, while also exploring potential bidirectional associations and identifying possible therapeutic targets. We employed Mendelian Randomization (MR) analysis to investigate a wide array of biological factors, including 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell characteristics, and 1,400 metabolites. Additionally, we utilized bioinformatics techniques such as constructing Protein-Protein Interaction (PPI) networks, performing Gene Ontology (GO) enrichment, and conducting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Our results indicated significant associations between CRC and 104 circulating proteins, 5 inflammatory proteins, 24 immune cell traits, and 28 metabolites. Through subnetwork analysis, we identified 15 central proteins, among which Tissue Inhibitor of Metalloproteinase 1 (TIMP1) showed notable variability in expression. This finding was computationally validated through survival analysis data from the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases. Furthermore, molecular docking studies confirmed TIMP1 as a promising drug target, demonstrating stable interactions with compounds such as meclizine and megestrol. Overall, this research enhances our understanding of CRC pathogenesis by emphasizing the roles of inflammation, immune response, and metabolic pathways, and it suggests TIMP1 as a particularly promising target for future therapeutic development.</p>

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Exploring the role of inflammation, immunity, and metabolism in colorectal cancer via mendelian randomization approach

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月8日

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  • Li Zhou,
  • Mingjing Liao,
  • Leilei Zhang,
  • Tingting Peng,
  • Chengyun Han,
  • Qiang Zeng,
  • Xuanrong Huan,
  • Anya Dai,
  • Zhongyan Gao,
  • Jie Li,
  • Jia Tang,
  • Jie Chen,
  • Yuan Li,
  • Jiwang Zhang

摘要

Colorectal cancer (CRC) is a prevalent type of cancer affecting the digestive system, characterized by a complex and not fully understood development process. Inflammation and metabolic processes are thought to play significant roles in both the initiation and progression of this disease. This study aimed to clarify the causal relationships between CRC and specific inflammatory proteins, immune cell types, and metabolites, while also exploring potential bidirectional associations and identifying possible therapeutic targets. We employed Mendelian Randomization (MR) analysis to investigate a wide array of biological factors, including 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell characteristics, and 1,400 metabolites. Additionally, we utilized bioinformatics techniques such as constructing Protein-Protein Interaction (PPI) networks, performing Gene Ontology (GO) enrichment, and conducting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Our results indicated significant associations between CRC and 104 circulating proteins, 5 inflammatory proteins, 24 immune cell traits, and 28 metabolites. Through subnetwork analysis, we identified 15 central proteins, among which Tissue Inhibitor of Metalloproteinase 1 (TIMP1) showed notable variability in expression. This finding was computationally validated through survival analysis data from the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases. Furthermore, molecular docking studies confirmed TIMP1 as a promising drug target, demonstrating stable interactions with compounds such as meclizine and megestrol. Overall, this research enhances our understanding of CRC pathogenesis by emphasizing the roles of inflammation, immune response, and metabolic pathways, and it suggests TIMP1 as a particularly promising target for future therapeutic development.