The EGR1-FOS Transcriptional Axis in Liver Fibrosis: An Integrated Bioinformatic Analysis of Disease Progression and Shared Molecular Signatures in Cirrhosis

Background: Liver fibrosis arises from chronic liver injury and remains a major clinical challenge due to its progression toward cirrhosis and hepatocellular carcinoma, as well as the absence of approved antifibrotic therapies. This study aimed to characterize the transcriptomic behavior of the EGR1-FOS axis in liver fibrosis and its evolution into hepatocellular carcinoma, and to identify genes shared between liver fibrosis and cirrhosis. Methods: An integrated bioinformatics approach was applied to GEO transcriptomic datasets. Differentially expressed genes in hepatic fibrosis were identified using GSE139602, GSE84044, and GSE49541, with GSE62232 as control when needed, while GSE14323 and GSE89377 were used to detect genes common with cirrhosis. GEPIA, TIMER, and TISCH2 were used to assess the involvement of the EGR1-FOS axis in hepatocellular carcinoma. External validation of EGR1 expression dynamics and its coregulation with FOS was performed using the GSE135251 dataset. Results: Eleven hub genes were identified, with emphasis on the EGR1-FOS axis. EGR1 expression fluctuated across liver fibrosis etiologies, whereas FOS was predominantly downregulated. A strong correlation between EGR1 and FOS (r = 0.77) was observed, remaining stable across fibrosis stages (all p < 0.001) and in hepatocellular carcinoma (r = 0.698, p = 1.81 × 10−55). Despite overall downregulation, both genes increased progressively with advancing fibrosis (EGR1: p = 0.0008–0.0035; FOS: p = 0.0001–0.0188). Four genes were shared between fibrosis and cirrhosis (SOX9, CD24, CXCR4, and CYP2C19). Conclusions: The EGR1-FOS axis acts as a dynamic regulator of liver fibrosis and its progression, and both this axis and the four shared genes identified may serve as valuable biomarkers and potential therapeutic targets.