Modified Project Summary/Abstract Section Obesity-induced liver injury is a significant health concern. In obesity, levels of circulating free fatty acids increase, which are taken up by the liver. Moreover, obesity-induced hyperinsulinemia causes pathway-selective insulin resistance, leading to reduced glucose uptake and increased gluconeogenesis and lipogenesis in the liver. Chronic alterations of these pathways contribute to lipotoxic stress, steatohepatitis, and hepatocellular injury. The resulting accumulation of excess fatty acids and cholesterol as lipid-droplets in hepatocytes is termed non-alcoholic fatty liver disease (NAFLD). With the progression of obesity, the injury and the associated activated macrophages together stimulate hepatic stellate cells (HSCs) into a fibrogenic phenotype, observed in non-alcoholic steatohepatitis (NASH). Sustained fibrogenesis can progress to cirrhosis, and a subset of cirrhosis patients develop hepatocellular carcinoma. Although no FDA-approved drugs are available to treat NASH yet, pathways that reduce body fat, insulin resistance, inflammation and fibrosis are being targeted. Inositol hexakisphosphate kinase-1 (IP6K1) generates the signaling inositol pyrophosphate molecule, 5-InsP7, which is a critical regulator of diverse metabolic functions including insulin secretion and signaling and energy metabolism. Our published studies demonstrated that IP6K1 promotes development and progression of obesity, insulin resistance and NAFLD/NASH. Furthermore, hepatic IP6K1 expression directly correlates with NASH and cirrhosis in humans. These data suggest that pharmacologic inhibition of IP6K1 could be a novel strategy to treat NAFLD/NASH. Here, we propose to utilize a well-established and productive team of researchers along with ligand-based drug design and enzymatic and cell-based assays to develop novel and potent IP6K1 inhibitors and validate their biochemical and functional activities in a mouse model of NAFLD/NASH. At the completion of this work, we expect to deliver a selective and orally available IP6K1 inhibitor suitable for in vivo efficacy studies and a viable method for large-scale synthesis of the compound.