Project Summary/Abstract Nonalcoholic steatohepatitis (NASH) is a progressive metabolic liver disease characterized by persistent liver injury, inflammation, and fibrosis. Reprogramming of intrahepatic signaling and liver microenvironment is a hallmark of NASH pathogenesis in mice and humans. However, the molecular nature of pathophysiological signaling that drives NASH progression remains an important unsolved question. To address this critical knowledge gap, we performed bulk and single-cell transcriptomic analysis on healthy and diet-induced NASH mouse livers. Our work revealed several transcriptomic signatures of NASH, liver cell heterogeneity and reprogramming during disease pathogenesis, and the landscape of intercellular crosstalk in the liver. Importantly, key features of NASH-associated reprogramming of the liver microenvironment and intrahepatic signaling in mice are notably conserved in human NASH. Hepatocytes respond to metabolic stresses in NASH by engaging adaptive and maladaptive signaling pathways that ultimately lead to liver steatosis and hepatocyte injury. In preliminary studies, we observed that hepatic expression of the truncated isoform of Tropomyosin receptor kinase B (TrkB), TrkB-T1, but not the full-length TrkB isoform, was selectively and markedly upregulated in mouse and human NASH. However, whether and how aberrant activation of hepatic TrkB-T1 signaling contributes to NASH pathogenesis has not been explored. Based on a body of preliminary data, we hypothesize that pathogenic activation of TrkB-T1 signaling sensitizes hepatocytes to stress-induced injury. In this proposal, we plan to investigate the role of TrkB-T1 in liver injury and NASH progression. We will explore cell-intrinsic and extrinsic mechanisms that mediate the effects of TrkB-T1 on NASH pathogenesis. Finally, we will explore the therapeutic potential of targeting this pathway for NASH treatment. Successful completion of this project will provide novel insights into the pathophysiology of NASH and generate critical preclinical data that will guide future translational work.