Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFbeta1 is a key upstream transcriptome regulator in AH and induces the use of HNF4alpha P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4alpha are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4alpha-dependent gene expression. We conclude that targeting TGFbeta1 and epigenetic drivers that modulate HNF4alpha-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.