Background: Alcoholic liver disease (ALD) is the main cause of cirrhosis worldwide and the main driver of health expenditure in hospitalized patients with liver disease in the US. The development of targeted therapies is hampered by a poor knowledge of the underlying mechanisms. It is unknown why some patients develop severe forms (i. e. alcoholic hepatitis -AH-) characterized by poor hepatocyte function. We hypothesize that global changes in the transcription factor activity may play a role in the development of severe forms. To test this hypothesis, we performed a functional analysis of RNAseq data from livers of patients with different ALD phenotypes compared to normal livers and cirrhosis. Methods: Liver biopsy specimens were collected from ALD patients in different stages of disease progression: early compensated ASH (N=12), non severe AH (N=11), severe AH non responders to steroids (N=9), severe AH responders (N=9) and liver explants from transplanted patients with severe AH (N=1l). Compensated HCV cirrhosis (n=10) and fragments from normal livers (N=10) were also studied. High-throughput RNA sequencing (RNA-Seq) was done. Unsupervised clustering (Bioconductor), gene ontology analysis (GSEA) and upstream regulator prediction (Ingenuity Pathway Analysis and Opossum) were performed. Results: Clustering analysis showed a specific transcriptome pattern across different ALD phenotypes. Major changes in ALD progression included the inhibition of hepatocyte biosynthetic pathways, drug metabolism, hepatocyte differentiation and the activation of cell proliferation, ECM deposition, inflammation and hypoxia. Importantly, AH mortality was associated with inhibition of cell responses to hypoxia and inflammation. Analysis of upstream regulators revealed profound transcription factor reprogramming Changes in the transcriptome along disease progression predicted a marked inhibition of nuclear factors responsible for hepatocyte differentiation (i. e. HNF4A, HNF1A and FOXA1), while factors implicated in cell damage and inflammation (i. e. NFATC2, STAT1 and NFKB1) were significantly activated Bioinformatic prediction showed an involvement of EGFR signaling in disease progression Studies in cultured hepatocytes demonstrated the inhibitory effect of EGFR activity on HNF4A expression and stability Conclusion: Progression to severe forms of ALD including AH is characterized by decreased activity of transcription factors implicated in hepatocyte differentiation. These results suggest that targeting transcription factors that maintain normal hepatocellular function represent a potential novel therapeutic strategy in these patients.