PROJECT SUMMARY Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), affects approximately 25% of adults and 10% of children in the United States. Multi-factorial in its pathogenesis, the clinical/histologic spectrum of MASLD encompasses steatosis, metabolic dysfunction- associated steatohepatitis (MASH), variable degrees of fibrosis, and cirrhosis. The presence of MASH or advanced fibrosis due to MASLD are associated with increased risks of hepatic decompensation, hepatocellular carcinoma (HCC), and death. There are currently no FDA-approved therapies for treatment of MASH. The sheer scale of the affected population creates an urgent need for effective treatments as well as non-invasive modalities and biomarkers that alone or in combination accurately 1) predict who is at high risk for disease progression in the MASLD population, 2) detect and stage MASLD, MASH, and liver fibrosis, 3) predict treatment response, as determined by ≥ 1-stage improvement in fibrosis or MASH resolution. Since its inception in 2002, the NASH CRN has worked collaboratively to characterize the natural history of MASLD, define its pathogenesis, and develop superior diagnostics and effective treatments. During the past funding cycle (2018-23), the CRN completed recruitment for the longitudinal adult and pediatric Database 2 registry (N=3,068) and the STOP-NAFLD trial (N=83). In addition, it initiated two studies: 1) Database 3, a longitudinal study of the etiology, natural history, diagnosis, treatment and prevention of MASLD and MASH with a goal of recruiting a diverse cohort, and 2) the Vitamin E Dosing Study (VEDS), a clinical trial with the primary aim of determining the minimum effective dose of Vitamin E for MASH. The NASH CRN’s highly characterized cohorts, including more than 700,000 biospecimens in the NIDDK repository, together with the investigator’s expertise in leveraging public-private partnerships, has allowed us to perform innovative clinical trials and pursuits in diagnostic development and validation that can only be addressed by engaging in a coordinated, longitudinal, comprehensive research consortium. The overriding primary objective of the NASH CRN continues to be clinical research on MASLD in children and adults. A secondary objective of high priority is to conduct translational research in MASH and MASLD and to develop superior diagnostics and treatments, with a focus on diagnostics that are non-invasive and treatments that are safe, affordable, effective and readily available. The specific aims proposed to achieve these objectives from the UCSD Clinical Center during the continuation of the NASH CRN are to 1) complete the Database 3 Study, 2) complete the VEDS Study, and 3) validate and advance development of novel non-invasive biomarkers for MASH, at-risk MASH, and advanced fibrosis or cirrhosis.