Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis

Introduction Non-alcoholic steatohepatitis (NASH), an advanced subtype of non-alcoholic fatty liver disease (NAFLD), has becoming the most important aetiology for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. This study were designed to explore novel genes associated with NASH. Methods Here, five independent Gene Expression Omnibus (GEO) datasets were combined into a single cohort and analyzed using network biology approaches. Results 11 modules identified by weighted gene co-expression network analysis (WGCNA) showed significant association with the status of NASH. Further characterization of four gene modules of interest demonstrated that molecular pathology of NASH involves the upregulation of hub genes related to immune response, cholesterol and lipid metabolic process, extracellular matrix organization, and the downregulation of hub genes related to cellular amino acid catabolic, respectively. After DEGs enrichment analysis and module preservation analysis, the Turquoise module associated with immune response displayed a remarkably correlation with NASH status. Hub genes with high degree of connectivity in the module, including CD53, LCP1, LAPTM5, NCKAP1L, C3AR1, PLEK, FCER1G, HLA-DRA and SRGN were further verified in clinical samples and mouse model of NASH. Moreover, single-cell RNA-seq analysis showed that those key genes were expressed by distinct immune cells such as microphages, natural killer, dendritic, T and B cells. Finally, the potential transcription factors of Turquoise module were characterized, including NFKB1, STAT3, RFX5, ILF3, ELF1, SPI1, ETS1 and CEBPA, the expression of which increased with NASH progression. Discussion In conclusion, our integrative analysis will contribute to the understanding of NASH and may enable the development of potential biomarkers for NASH therapy.

• Publication year

  2023

• Venue

  Frontiers in Endocrinology

• Publication date

  2023-03-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fendo.2023.1115890PMID 37008925PMCID 10061151
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis through degradating CDC42

  2023cited by this paper
• Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice

  2023cited by this paper
• A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

  2022influential reference
• Multiomics study of nonalcoholic fatty liver disease

  2022cited by this paper
• Significance of m6A regulatory factor in gene expression and immune function of osteoarthritis

  2022cited by this paper
• IL6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease.

  2022cited by this paper
• Genome-Scale CRISPR screen identifies LAPTM5 driving lenvatinib resistance in hepatocellular carcinoma

  2022influential reference
• Comprehensive analysis of endoplasmic reticulum-related and secretome gene expression profiles in the progression of non-alcoholic fatty liver disease

  2022cited by this paper
• Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis

  2022cited by this paper
• Genetic polymorphism of HLA-DRA and alcohol consumption affect hepatitis development in the Korean population

  2022cited by this paper
• Identification of Key Biomarkers and Immune Infiltration in Liver Tissue after Bariatric Surgery

  2022cited by this paper
• The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages

  2022cited by this paper
• Risk assessment with gut microbiome and metabolite markers in NAFLD development

  2022cited by this paper
• Construction and Analysis of a Joint Diagnosis Model of Random Forest and Artificial Neural Network for Obesity

  2022cited by this paper
• Regulation of the Late Onset alzheimer’s Disease Associated HLA-DQA1/DRB1 Expression

  2022cited by this paper
• Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH

  2021cited by this paper
• Multiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis

  2021cited by this paper
• TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis.

  2021cited by this paper
• Bioinformatics Analysis Explores Potential Hub Genes in Nonalcoholic Fatty Liver Disease

  2021cited by this paper
• A network-based approach reveals the dysregulated transcriptional regulation in non-alcoholic fatty liver disease

  2021cited by this paper
• Long non-coding RNA ILF3-AS1 facilitates hepatocellular carcinoma progression by stabilizing ILF3 mRNA in an m6A-dependent manner

  2021cited by this paper
• Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities

  2021cited by this paper
• Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication.

  2021cited by this paper
• Tripartite motif 16 ameliorates nonalcoholic steatohepatitis by promoting the degradation of phospho-TAK1.

  2021cited by this paper
• LncRNA ILF3-AS1 promotes cell migration, invasion and EMT process in hepatocellular carcinoma via the miR-628-5p/MEIS2 axis to activate the Notch pathway.

  2021cited by this paper
• ILF3 Is a Negative Transcriptional Regulator of Innate Immune Responses and Myeloid Dendritic Cell Maturation

  2021cited by this paper
• XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis

  2021cited by this paper
• Core liver homeostatic co-expression networks are preserved but respond to perturbations in an organism- and disease-specific manner.

  2021cited by this paper
• Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress.

  2021cited by this paper
• Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort.

  2020cited by this paper
• Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome

  2020cited by this paper
• Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis

  2020cited by this paper
• RFX5 promotes the progression of hepatocellular carcinoma through transcriptional activation of KDM4A

  2020cited by this paper
• Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder

  2020cited by this paper
• Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease

  2020cited by this paper
• Leukocyte Tetraspanin CD53 Restrains α3 Integrin Mobilization and Facilitates Cytoskeletal Remodeling and Transmigration in Mice

  2020cited by this paper
• Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages.

  2020cited by this paper
• Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis.

  2020cited by this paper
• Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis

  2019cited by this paper
• Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis

  2019cited by this paper
• Metformin alleviates inflammatory response in non-alcoholic steatohepatitis by restraining signal transducer and activator of transcription 3-mediated autophagy inhibition in vitro and in vivo.

  2019cited by this paper
• Bone marrow‐derived macrophage contributes to fibrosing steatohepatitis through activating hepatic stellate cells

  2019cited by this paper
• Past, present and future perspectives in nonalcoholic fatty liver disease

  2019cited by this paper
• A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

  2019cited by this paper
• From NASH to HCC: current concepts and future challenges

  2019influential reference
• Regulatory factor X5 promotes hepatocellular carcinoma progression by transactivating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta and suppressing apoptosis

  2019cited by this paper
• Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis.

  2019cited by this paper
• Integrated Analysis of Multiple Microarray Studies to Identify Novel Gene Signatures in Non-alcoholic Fatty Liver Disease

  2019cited by this paper
• Resolving the fibrotic niche of human liver cirrhosis at single cell level

  2019influential reference
• A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome

  2019cited by this paper
• Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH)

  2019cited by this paper
• ChEA3: transcription factor enrichment analysis by orthogonal omics integration

  2019cited by this paper
• Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC

  2018cited by this paper
• Comprehensive integration of single cell data

  2018cited by this paper
• Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

  2018cited by this paper
• Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women

  2018cited by this paper
• Molecular Phenomics and Metagenomics of Hepatic Steatosis in Non-Diabetic Obese Women

  2018cited by this paper
• Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease.

  2018cited by this paper
• Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations

  2018cited by this paper
• A Protein‐Truncating HSD17B13 Variant and Protection from Chronic Liver Disease

  2018cited by this paper
• The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases

  2018cited by this paper
• The transcription factor RFX5 is a transcriptional activator of the TPP1 gene in hepatocellular carcinoma.

  2017cited by this paper
• TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions

  2017cited by this paper
• DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants

  2016cited by this paper
• A novel glycobiomarker, Wisteria floribunda agglutinin macrophage colony‐stimulating factor receptor, for predicting carcinogenesis of liver cirrhosis

  2016cited by this paper
• Global epidemiology of nonalcoholic fatty liver disease—Meta‐analytic assessment of prevalence, incidence, and outcomes

  2016cited by this paper
• Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

  2016cited by this paper
• Nuclear factor 90 uses an ADAR2-like binding mode to recognize specific bases in dsRNA

  2015cited by this paper
• Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis1

  2015cited by this paper
• The Transcriptional Repressor BLIMP1 Curbs Host Defenses by Suppressing Expression of the Chemokine CCL8

  2014cited by this paper
• The serum proteome of nonalcoholic fatty liver disease: A multimodal approach to discovery of biomarkers of nonalcoholic steatohepatitis

  2014cited by this paper
• Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

  2014influential reference
• HLA DQB1 alleles are related with nonalcoholic fatty liver disease

  2014cited by this paper
• C3a Receptor Antagonist Ameliorates Inflammatory and Fibrotic Signals in Type 2 Diabetic Nephropathy by Suppressing the Activation of TGF-β/smad3 and IKBα Pathway

  2014cited by this paper
• Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types

  2014cited by this paper
• Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

  2014cited by this paper
• Association between liver‐specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease

  2013cited by this paper
• NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses.

  2013cited by this paper
• Effects of NFKB1 and NFKBIA Gene Polymorphisms on Hepatocellular Carcinoma Susceptibility and Clinicopathological Features

  2013cited by this paper
• NCBI GEO: archive for functional genomics data sets—update

  2012cited by this paper
• LAPTM5 Protein Is a Positive Regulator of Proinflammatory Signaling Pathways in Macrophages*

  2012cited by this paper
• Is My Network Module Preserved and Reproducible?

  2011cited by this paper
• Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

  2011cited by this paper
• Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study.

  2011cited by this paper
• Pathology of nonalcoholic fatty liver disease

  2010cited by this paper
• Resolution of renal inflammation: a new role for NF-kappaB1 (p50) in inflammatory kidney diseases.

  2009cited by this paper
• IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat

  2009cited by this paper
• Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

  2009cited by this paper
• Structuring and extracting knowledge for the support of hypothesis generation in molecular biology

  2009influential reference
• Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response

  2008cited by this paper
• Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

  2008cited by this paper
• WGCNA: an R package for weighted correlation network analysis

  2008cited by this paper
• NF90 regulates inducible IL-2 gene expression in T cells

  2007cited by this paper
• Pathology of nonalcoholic fatty liver disease.

  2007cited by this paper
• Conservation and evolution of gene coexpression networks in human and chimpanzee brains

  2006cited by this paper
• A General Framework for Weighted Gene Co-Expression Network Analysis

  2005cited by this paper
• From the Cover: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

  2005cited by this paper
• Functions of NF-?B1 and NF-?B2 in immune cell biology

  2004cited by this paper
• Functions of NF-kappaB1 and NF-kappaB2 in immune cell biology.

  2004cited by this paper
• Reciprocal regulation of inflammation and lipid metabolism by liver X receptors

  2003cited by this paper

• A Multi-Omics Approach to Decipher the Protective Mechanism of Myristica Fragrans Against Acute Lung Injury.

  2026cites this paper
• DPP4 inhibition affects metabolism and inflammation associated pathways in hiPSC-derived steatotic HLCs

  2026cites this paper
• Transcriptional and Pathway Level Heterogeneity in Luminal A Breast Cancer: A Framework for Precision Therapy.

  2026cites this paper
• ILF3 inhibits p-AMPK expression to drive non-alcoholic fatty liver disease progression

  2025cites this paper
• Investigation of the Pathogenesis of Liver Fibrosis Associated with Type 2 Diabetes Mellitus via Bioinformatic Analysis

  2025cites this paper
• Identification of MEOX1 as a potential target in metabolic dysfunction-associated steatohepatitis-related liver fibrosis

  2025cites this paper
• Potential diagnostic marker gene set for non-alcoholic steatohepatitis associated hepatocellular carcinoma with lymphocyte infiltration

  2025cites this paper
• Identification of regulatory cell death-related genes during MASH progression using bioinformatics analysis and machine learning strategies

  2025cites this paper
• Macrophage inhibition in the alleviation of nonalcoholic steatohepatitis caused by bariatric surgery

  2025cites this paper
• Role of the E26 transformation specific transcription factor family in metabolic disorders

  2025cites this paper
• Multi-Omics Analysis Identifies Immune Regulatory Networks in Sepsis-Associated Liver Injury: Experimental Validation and Clinical Relevance

  2025cites this paper
• Is There a Diagnostic Miracle on the Horizon? Emerging Biomarkers in MASLD

  2025cites this paper
• ANTIFIBROTIC STRATEGY IN THE TREATMENT OF CHRONIC LIVER DISEASES

  2025cites this paper
• Uncovering biomarkers and molecular pathways linking NAFLD and AIS: Insights from bioinformatic analysis and experiment

  2025cites this paper
• Ahnak and Nckap1l as potential diagnostic biomarkers and therapeutic targets in Landiolol-mediated sepsis treatment

  2025cites this paper
• Identification of the common pathogenesis of Alzheimer's and nonalcoholic fatty liver disease and exploration of their relationship with immune cells.

  2025cites this paper
• The immune microenvironment related biomarker CCL18 for patients with gout by comprehensive analysis

  2024cites this paper
• Deciphering Mechanisms of Adipocyte Differentiation in Abdominal Fat of Broilers

  2024cites this paper
• K-hyperparameter tuning in high-dimensional genomics using joint optimization of deep differential evolutionary algorithm and unsupervised transfer learning from intelligent GenoUMAP embeddings

  2024cites this paper
• Integrative analysis identifies oxidative stress biomarkers in non-alcoholic fatty liver disease via machine learning and weighted gene co-expression network analysis

  2024cites this paper
• Machine learning-based integration identifies the ferroptosis hub genes in nonalcoholic steatohepatitis

  2024cites this paper
• Atrial Proteomic Profiling Reveals a Switch Towards Profibrotic Gene Expression Program in CREM-IbΔC-X Mice with Persistent Atrial Fibrillation

  2024cites this paper
• Atrial proteomic profiling reveals a switch towards profibrotic gene expression program in CREM-IbΔC-X mice with persistent atrial fibrillation.

  2024cites this paper
• Identifying MS4A6A+ macrophages as potential contributors to the pathogenesis of nonalcoholic fatty liver disease, periodontitis, and type 2 diabetes mellitus

  2024cites this paper
• IL-1β and CXCR4 as Potential Therapeutic Targets for Alzheimer’s Disease

  2024cites this paper
• Identification of Immune-Related Gene Signature in Schizophrenia

  2024influential citation
• Potential Shared Mitochondrial-Related Gene Signatures and Molecular Mechanisms Between Polycystic Ovary Syndrome (PCOS) and Major Depressive Disorder (MDD): Evidence from Transcriptome Data and Machine Learning

  2024cites this paper
• The function and mechanism of LAPTM5 in diseases.

  2024cites this paper
• Analysis of macrophage polarization and regulation characteristics in ovarian tissues of polycystic ovary syndrome

  2024cites this paper
• Unveiling functionality and conducting two-sample mendelian randomization on WGCNA-identified oxidative stress-related hub genes in metabolic dysfunction-associated fatty liver disease

  2024cites this paper
• Identification of Shared and Unique Key Biomarkers of Alcohol Liver Cirrhosis and Non-Alcoholic Steatohepatitis Through Machine Learning Network-Based Algorithms

  2024cites this paper
• Inhibiting DPP4 activity protects hiPSC-derived steatotic HLCs by supporting fatty acid and purine metabolism and dampening in�ammation

  year unknowncites this paper
• World Journal of Hepatology

  year unknowncites this paper