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Research Article
Functional investigation and two-sample Mendelian randomization study of non-alcoholic fatty liver disease hub genes obtained by WGCNA
1 Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
2 Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
Address correspondence to:
Yunchuan Yang
Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province,
China
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Article ID: 100110Z04YY2026
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Yang Y, Zhao Z, Huo J, Guo K, Ma X, Zhou C, Sun T, Zhou L. Functional investigation and two-sample Mendelian randomization study of non-alcoholic fatty liver disease hub genes obtained by WGCNA. Int J Hepatobiliary Pancreat Dis 2026;16(1):8–14.ABSTRACT
Aims: Non-alcoholic fatty liver disease (NAFLD) poses significant health risks with progression to severe liver pathologies, while its molecular mechanisms remain unclear. This study aimed to identify NAFLD hub genes and evaluate their clinical and causal value.
Methods: We performed differential expression analysis and weighted gene co-expression network analysis (WGCNA) on GSE89632 to screen NAFLD-related modules and hub genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A nomogram model and Receiver Operating Characteristic (ROC) curves were constructed for diagnostic efficacy assessment, and the correlation between FOS (Fos proto-oncogene) expression and immune cell infiltration was analyzed. Two-sample Mendelian randomization (MR) was used to verify the causal relationship between FOS and NAFLD susceptibility.
Results: 115 key genes were obtained from the intersection of WGCNA module genes and differentially expressed genes (DEGs), enriched in fat cell differentiation, Tumor necrosis factor (TNF)/Mitogen-activated protein kinase (MAPK) signaling pathways, etc. The top 10 upregulated hub genes were FOS, JUN, Nuclear receptor subfamily 4 group A member 1 (NR4A1), JunB proto-oncogene, AP-1 transcription factor subunit (JUNB), Early growth response 1 (EGR1), MYC proto-oncogene, bHLH transcription factor (MYC), Interleukin 1 beta (IL1B), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8 (CXCL8), Prostaglandin-endoperoxide synthase 2 (PTGS2). The nomogram model had good NAFLD prediction performance, and FOS, JUN, MYC had an AUC of 1.000 for diagnosis. FOS expression correlated with immune cell infiltration in NAFLD. The Mendelian randomization analysis found no causal link between FOS and NAFLD risk (OR = 0.997, 95% CI = 0.947–1.049, p = 0.898).
Conclusion: We identified 10 NAFLD-associated hub genes. These genes support early NAFLD diagnosis. They clarify NAFLD molecular mechanisms.
Keywords: FOS, Mendelian randomization, Non-alcoholic fatty liver disease, WGCNA
SUPPORTING INFORMATION
Acknowledgments
The authors thank all participants and researchers involved in the GWAS studies used in this research for their valuable contributions. This study was supported by the Natural Science Youth Project of Bengbu Medical University (No. 2024byzd085) and the 2024 Science and Technology Innovation Guidance Program of Bengbu City (No. 18).
Artificial Intelligence (AI) Use Statement
No generative AI technology was used in the conception, design, data analysis, interpretation, or writing of this manuscript. All content was created and reviewed by the authors, who take full responsibility for the accuracy and integrity of the work.
Yunchuan Yang - Substantial contributions to conception and design, Drafting the article, Final approval of the version to be published
Zhengxin Zhao - Acquisition of data, Analysis of data, Drafting the article, Final approval of the version to be published
Junyi Huo - Acquisition of data, Analysis of data, Drafting the article, Final approval of the version to be published
Ke Guo - Acquisition of data, Analysis of data, Drafting the article, Final approval of the version to be published
Xiang Ma - Substantial contributions to conception and design, Revising it critically for important intellectual content, Final approval of the version to be published
Chi Zhou - Interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Tao Sun - Acquisition of data, Analysis of data, Drafting the article, Final approval of the version to be published
Lei Zhou - Interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of SubmissionThe corresponding author is the guarantor of submission.
Source of SupportNone
Consent StatementWritten informed consent was obtained from the patient for publication of this article.
Data AvailabilityAll relevant data are within the paper and its Supporting Information files.
Conflict of InterestAuthors declare no conflict of interest.
Copyright© 2026 Yunchuan Yang et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.
