Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease in Western countries. ALD is associated with increased mortality due to a broad spectrum of hepatic pathologies ranging from simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. Recent studies have drawn attention to other factors contributing to ALD, including alterations in the vasculature, portal tract inflammation and peribiliary fibrosis, and ductular reaction (i.e., activation of the neuroendocrine phenotype of cholangiocytes). However, very little information is known about the effects of alcohol on biliary epithelial cells (i.e., cholangiocytes). Substance P (SP) is a neuropeptide secreted predominantly from sensory neurons and is known to play a key role in neuroinflammation via the recruitment and activation of immune cells. Previous studies have shown an upregulation of the SP/NK1R axis in cholangiocytes in response to liver injury due to cholestasis and that SP regulates cholangiocyte proliferation via cAMP/PKA signaling. SP has been shown to increase hepatic fibrosis via differential changes in cholangiocytes and hepatic stellate cell (HSCs) senescence. However, the SP/NK1R axis's role in ALD has not been explored. Based on novel preliminary data, the central hypothesis is that ALD-induced ductular reaction triggers a neuroendocrine phenotype in cholangiocytes whereby secretion of SP stimulates hepatic steatosis and fibrosis and increases infiltration and activation of immune cells occurs during the progression of ALD in proposed. To address the central hypothesis, two specific aims are proposed: 1) determine the expression and distribution of SP/NK1R axis during the progression of ALD in human samples and a mouse model of alcohol- induced liver injury; and 2) determine the therapeutic potential of the knockdown and/or pharmacological inhibition of the SP/NK1R axis in a mouse model of ALD and human ALD-derived liver organoids. The expected outcome of this work is an understanding of the role of the SP/NK1 axis and downstream signaling mechanisms in the pathogenesis of ALD. The successful completion of the proposed studies will have a significant positive impact on the knowledge of factors regulating ductular reaction observed in ALD and lay the groundwork for developing novel therapeutic approaches for ALD.