Transcriptomics Analysis Reveals Dual Axes of Metabolic and Immune Dysregulation in the Progression of NAFLD to HCC

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a global health concern, with a portion of patients progressing to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The molecular mechanism driving this progression is elusive. Here, we have identified key pathogenic genes associated with this progression using transcriptomic data from three microarray datasets GSE164760, GSE25097, and GSE4845. Collectively, there are 798 liver tissue samples across Chinese, German, and multi‐institutional cohorts. The datasets span the NAFLD spectrum including healthy, early NAFLD, NASH, cirrhosis, and NASH‐associated HCC. A differential gene expression (DEG) analysis of these data suggests a list of genes consistently dysregulated across disease stages, reflecting potential biomarkers or contributors to the disease progression. Our gene ontology (GO) based enrichment analysis reveals that dysregulated DEGs are primarily associated with metabolic, inflammatory, immune, and epigenetic pathways. We have constructed a protein–protein interaction network of DEGs for each dataset and predicted the respective hub proteins that are likely to exert significant influence over disease‐relevant pathways linked to neurogenic signaling and chromatin modification, underscoring stage‐specific molecular events in NAFLD progression. Further, we have performed transcription factor (TF) enrichment analysis that suggests TP53, FOSB, STAT3, CREB1, and ATF2 would be potentially driving changes observed in DEGs. Our results suggest that the dual axes of metabolic activation and immune suppression would be convergent themes in NASH–HCC pathogenesis. In addition, we have constructed a gene regulatory network for key TFs. Genes such as FASN, SAA1, and HLA‐DRA, and regulators like SREBF2 and TP53, may serve as candidate markers for disease stratification or intervention . Highlights This is the first study to perform a comprehensive analysis of gene expression changes and its regulation during the various stages of NAFLD spectrum including healthy, early NAFLD, NASH, NASH‐cirrhosis, and NASH‐HCC. Early and persistent activation of metabolic and inflammatory processes with concurrent suppression of immune activation is observed supporting a role in oncogenesis.