Morbidity and mortality in alcohol-related liver diseases (ALD) are caused by severe alcohol-induced steatohepatitis (SAH), cirrhosis, and liver cancer. Effective therapies are lacking because the mechanisms driving the pathogenesis and progression of these conditions are unclear. This research program has evaluated the general hypothesis that bad outcomes of alcohol-induced liver injury result from deregulated repair mechanisms that cause defective regeneration of mature hepatocytes. Our prior results indicate that effective liver regeneration requires reactivating fetal programs to nurture the outgrowth of liver progenitors, but then silencing these programs so that the liver matures. Thus, we will next evaluate the hypothesis that alcohol-related liver diseases progress because mechanisms controlling when fetal programs are switched on and off in adult liver cells are dysregulated. We have evidence that liver failure in human SAH results from over-activation of fetal programs. Conversely, our pre-clinical data suggest that cirrhosis evolves when adult programs are not suppressed sufficiently for injured livers to regenerate. To define tractable mechanisms that control adult-fetal “switching” in hepatocytes of alcohol-injured livers we will leverage our recently published data which show that the RNA binding protein ESRP2 is critically important for switching on the adult program in developing livers, and that over-expressing ESRP2 blocks adult liver regeneration. ESRP2 regulates the splicing of ~20% of hepatocyte RNAs, generating splice variants that encode functional differences in proteins that control hepatocyte proliferation and differentiation. Aims 1 and 2 will use ESRP2-knockout and over-expressing mice to determine how manipulating fetal RNA splicing programs impacts progression of alcohol-induced liver injury. In Aim 3 next generation sequencing and computational analysis will identify a conserved repertoire of RNA binding proteins, RNA splice variants, and liver genes that change in response to alcohol-induced liver injury in both mice and humans, thereby revealing novel therapeutic targets to improve recovery from ALD.