PROJECT SUMMARY The goal of this proposal is to advance our understanding of the mechanism for increased periportal collagen deposition, a sign of developing fibrosis, in the liver of the fetus with fetal growth restriction (FGR) and the impact on future liver metabolic disease. Children born with FGR have a higher risk of developing metabolic dysfunction- associated steatotic liver disease (MASLD) and fibrosis in childhood and adulthood. A distinct feature of MASLD presentation in pediatric patients, and one that is higher in FGR offspring, is localized fibrosis in periportal regions. Previous studies demonstrate that hypoxemia-induced oxidative stress promotes hepatic fibrosis in animal models. Yet, there remains a gap in our understanding of how oxidative stress in the fetal liver may promote a fibrotic niche and future susceptibility to liver disease associated with fibrosis. Our preliminary data indicate that FGR fetal sheep have increased hepatic periportal collagen deposition and increased markers of oxidative stress signaling. In addition, our preliminary data in fetal sheep exposed to long-term hypoxia show an increase in hepatic periportal fibrosis. I hypothesize that hypoxemia-induced oxidative stress in the FGR fetus produces cell-specific and regional effects in the fetal liver that initiate periportal fibrosis. Overall, this proposal will provide critical information for how FGR promotes hepatic fibrosis that persists postnatally. Aim 1 will Identify cell-specific and regional gene expression signatures in the fetal liver in response to FGR. Aim 2 will test if FGR and hypoxemia promote intrinsic fibrogenic capacity in hepatic stellate cells and test whether treatment of an antioxidant, N-acetylcysteine, prevents hypoxia-induced activation. Aim 3 will determine if hepatic fibrosis persists in postnatal lambs born with FGR. Expected Outcomes: This proposal will characterize the impact of FGR on oxidative stress and fibrosis in the fetal liver. Importantly, completion of this proposal will provide me with training in liver physiology and metabolism, bioinformatics, advanced histology, models to study fetal development, hepatic stellate cell culture, and scientific writing to help me achieve my career goal as a tenure-track assistant professor specialized in the fetal developmental programming of immunometabolism. Impact: The aims in this proposal will be used to help understand how fibrosis develops in postnatal liver of FGR offspring and determine future mechanistic experiments used to investigate fetal origins of fibrosis.