Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics
Abstract Background The causal relationship between inflammatory biomarkers and hepatocellular carcinoma (HCC) risk remains unclear. This study aimed to investigate the causal associations between various inflammation-related biomarkers and HCC risk using Mendelian randomization (MR) analysis, compl...
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Springer
2025-08-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-03357-7 |
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| author | GuangXin Shao Xiao Yun Hongyue Xie Beicheng Sun |
| author_facet | GuangXin Shao Xiao Yun Hongyue Xie Beicheng Sun |
| author_sort | GuangXin Shao |
| collection | DOAJ |
| description | Abstract Background The causal relationship between inflammatory biomarkers and hepatocellular carcinoma (HCC) risk remains unclear. This study aimed to investigate the causal associations between various inflammation-related biomarkers and HCC risk using Mendelian randomization (MR) analysis, complemented by single-cell transcriptomic validation. Methods We conducted comprehensive MR analyses using multiple statistical approaches including MR Egger, weighted median, inverse variance weighted, weighted mode, and simple mode methods to evaluate causal relationships between inflammatory biomarkers and HCC risk. Over 20–30 single nucleotide polymorphisms (SNPs) were employed as instrumental variables for each biomarker. Single-cell RNA sequencing data from four HCC samples (BT1306, BT1307, scrSOL004, scrSOL006) were analyzed to validate findings through cellular heterogeneity analysis, cell-cell communication networks, and pathway enrichment analysis. Results MR analysis identified differential causal effects of inflammatory biomarkers on HCC risk. Protective factors included CCL7 (OR: 0.524–0.714), CCL11 (OR: 0.660–0.752), IFN-gamma (OR: 0.657), NT-3 (OR: 0.520), and TWEAK_TNFSF12 (OR: 0.804), suggesting these factors may reduce HCC risk through immune modulation. Conversely, risk factors comprised CASP-8 (OR: 1.530), CD5 (OR: 2.079), FGF-21 (OR: 2.052), and CCL2 (OR: 2.440), with CCL2 showing the strongest pathogenic association. Single-cell analysis successfully identified 29 distinct cell subpopulations and revealed complex intercellular communication networks involving MIF, MK, and ncWNT signaling pathways. CCL2 and CCL8 demonstrated significant positive correlation (r = 0.4362, p < 0.001) across multiple cell types, with fibroblasts and malignant cells serving as central communication hubs. Conclusions This study provides robust genetic evidence for causal relationships between specific inflammatory biomarkers and HCC risk through MR analysis. |
| format | Article |
| id | doaj-art-a6d8d0c9c0a645669b4fe67f72dcaa03 |
| institution | DOAJ |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-a6d8d0c9c0a645669b4fe67f72dcaa032025-08-20T03:05:05ZengSpringerDiscover Oncology2730-60112025-08-0116112010.1007/s12672-025-03357-7Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomicsGuangXin Shao0Xiao Yun1Hongyue Xie2Beicheng Sun3Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing UniversityDepartment of Hepatopancreatobiliary Surgery, The Third Affiliated Hospital of Soochow UniversityDepartment of Hepatobiliary Surgery, Graduate School of Peking Union Medical College, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing UniversityAbstract Background The causal relationship between inflammatory biomarkers and hepatocellular carcinoma (HCC) risk remains unclear. This study aimed to investigate the causal associations between various inflammation-related biomarkers and HCC risk using Mendelian randomization (MR) analysis, complemented by single-cell transcriptomic validation. Methods We conducted comprehensive MR analyses using multiple statistical approaches including MR Egger, weighted median, inverse variance weighted, weighted mode, and simple mode methods to evaluate causal relationships between inflammatory biomarkers and HCC risk. Over 20–30 single nucleotide polymorphisms (SNPs) were employed as instrumental variables for each biomarker. Single-cell RNA sequencing data from four HCC samples (BT1306, BT1307, scrSOL004, scrSOL006) were analyzed to validate findings through cellular heterogeneity analysis, cell-cell communication networks, and pathway enrichment analysis. Results MR analysis identified differential causal effects of inflammatory biomarkers on HCC risk. Protective factors included CCL7 (OR: 0.524–0.714), CCL11 (OR: 0.660–0.752), IFN-gamma (OR: 0.657), NT-3 (OR: 0.520), and TWEAK_TNFSF12 (OR: 0.804), suggesting these factors may reduce HCC risk through immune modulation. Conversely, risk factors comprised CASP-8 (OR: 1.530), CD5 (OR: 2.079), FGF-21 (OR: 2.052), and CCL2 (OR: 2.440), with CCL2 showing the strongest pathogenic association. Single-cell analysis successfully identified 29 distinct cell subpopulations and revealed complex intercellular communication networks involving MIF, MK, and ncWNT signaling pathways. CCL2 and CCL8 demonstrated significant positive correlation (r = 0.4362, p < 0.001) across multiple cell types, with fibroblasts and malignant cells serving as central communication hubs. Conclusions This study provides robust genetic evidence for causal relationships between specific inflammatory biomarkers and HCC risk through MR analysis.https://doi.org/10.1007/s12672-025-03357-7Mendelian randomizationHepatocellular carcinomaInflammatory biomarkersSingle-cell transcriptomics |
| spellingShingle | GuangXin Shao Xiao Yun Hongyue Xie Beicheng Sun Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics Discover Oncology Mendelian randomization Hepatocellular carcinoma Inflammatory biomarkers Single-cell transcriptomics |
| title | Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics |
| title_full | Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics |
| title_fullStr | Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics |
| title_full_unstemmed | Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics |
| title_short | Mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk: genetic causality and single-cell transcriptomics |
| title_sort | mendelian randomization analysis of inflammatory biomarkers and hepatocellular carcinoma risk genetic causality and single cell transcriptomics |
| topic | Mendelian randomization Hepatocellular carcinoma Inflammatory biomarkers Single-cell transcriptomics |
| url | https://doi.org/10.1007/s12672-025-03357-7 |
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