Alcohol-associated liver disease (ALD) is a leading cause of chronic liver diseases and the predominant cause of liver-related mortality in Western countries. Patients with ALD may develop a wide spectrum of liver pathologies from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and eventually hepatocellular carcinoma. Extensive research has been performed to study the impact of alcohol on hepatocytes, stellate cells, and immune cells including Kupffer cells in ALD, but little is known about how alcohol affects biliary epithelial cells (i.e., cholangiocytes), and how biliary damage may contribute to the early and late stages of ALD pathogenesis. Recent studies have indicated that ductular reaction occurs in patients with alcoholic hepatitis. We have previously shown in other models of hepatic damage that the secretin (Sct)/secretin receptor (SR) axis is upregulated and plays a critical role in ductular reaction/biliary senescence as well as contributes to hepatic fibrosis. Our preliminary data that ALD-induced ductular reaction, biliary senescence, inflammation, and fibrosis were ameliorated in mice lacking the Sct/SR axis, indicating a crucial role for the SCT/SR axis during the pathogenesis of ALD. We propose the novel central hypothesis that the SCT/SR signaling axis is a key for mediating the senescent, profibrogenic biliary phenotype that contributes to the progression of hepatic inflammatory cell infiltration and subsequent fibrosis during the course of the pathogenesis of ALD. To test our hypothesis, we will pursue the following specific aims. In Specific aim #1, we will determine that activation of SCT/SR axis-dependent ductular reaction and biliary senescence plays a key role in the induction of liver inflammation that drives hepatic fibrosis during the pathogenesis of ALD. In specific aim #2, we will evaluate if therapeutic inhibition of the SCT/SR axis can prevent and limit the progression of ALD. Completion of the proposed studies will elucidate the translational mechanism on the role of SCT/SR axis in the promotion of local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype, biliary senescence, hepatobiliary inflammation and fibrosis during the progression of ALD.