ABSTRACT Liver fibrosis and cirrhosis are widely prevalent globally and associated with high morbidity and mortality. A hallmark of liver fibrosis is hepatic stellate cells (HSC) activation. While there are many transcriptional and translational changes associated with HSC activation, how these changes are initiated and regulated is still not well understood. We recently demonstrated that BMP-SMAD1/5/8 signaling in hepatocytes is not only the central pathway that maintains iron homeostasis by regulating the iron hormone hepcidin, but also plays a protective role in liver fibrosis, as mice with hepatocyte SMAD1/5/8 signaling deficiency display spontaneous liver fibrosis. However, the mechanisms of hepatocyte SMAD1/5/8-mediated protection in liver fibrosis is not known. In addition, the function of SMAD1/5/8 signaling in HSC is completely missing. The overall objective of this proposal is to understand the role of SMAD1/5/8 signaling in hepatocytes and HSCs in liver fibrosis. My preliminary data suggest a role for hepatocyte SMAD1/5/8 signaling in regulating the production of wntless to control secretion of Wnt ligands, which have paracrine actions to activate HSCs. My data also suggest that intrinsic SMAD1/5/8 signaling within HSCs may also be protective against HSC activation and liver fibrosis. In Specific Aim I, I will use in vitro and in vivo approaches to determine the role of hepatocyte wntless in HSC activation and liver fibrosis in hemochromatosis and NASH models. I will also perform secretomics to identify the hepatocytes secreted paracrine modulators that activate HSCs. In Specific Aim II, I will used primary HSCs and HSC specific conditional knockout mice to investigate the intrinsic role of SMAD1/5/8 in HSC activation and liver fibrosis. This proposal will not only fill in the gaps in understanding the pathology of liver fibrosis in hemochromatosis but will also advance the liver fibrosis field more broadly by providing new insights into hepatocyte-HSCs intercellular communication and HSCs biology, more importantly, will pave the way for new clinical treatments for liver fibrosis and cirrhosis. My long-term career goal is to successfully establish a research group and obtain a tenure-track faculty position in a leading academic or hospital-based research institute. My future research goals are to bridge the gaps between iron disorders and chronic liver diseases through investigating the direct biological mechanisms by combining my expertise in iron homeostasis with the new training opportunities in liver histopathology, gene editing and proteomics techniques described in this proposal.