This application is a competitive renewal of the Cleveland site and subsites of the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN). The term non-alcoholic fatty liver disease (NAFLD) and NASH have now been suggested by various academic and clinical societies to be replaced with the terms metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction associated steatohepatitis (MASH). However, given the continued widespread use of the terms, for this application, we will refer to these diseases as NAFLD/NASH. This renewal addresses the major goals of the program announcement (RFA 23-515) that include completion of the ongoing studies and analyze the existing datasets. The primary goal of the NASH CRN is to address the key unmet needs in the field that include: Improvement of our understanding of the pathogenesis and natural course of the disease; Development of non-invasive biomarkers to predict severity and progression of the disease; and Identify safe and effective therapies. Towards these goals, in this competitive renewal we will complete the enrollment, execution and analyses of the prospective database of well characterized adults and children with NAFLD/NASH. In addition, our robust and productive interaction with the Cincinnati Children’s Hospital has allowed us to enroll and follow children with NAFLD. Given the lack of licensed/approved treatments for NASH, and the high public health significance, the ongoing vitamin E dosing study (VEDS) is a randomized, double masked clinical trial to identify the lowest effective dose of vitamin E using non-invasive outcome measures. We will also utilize the available clinical data, biosamples, histological, and imaging data to develop and validate the underlying mechanisms and potential biomarkers for the diagnosis and staging of NASH. The Cleveland site has consistently been the highest enrolling site with exceptionally high quality data accumulation since inception in both the database (cohort) and randomized clinical trials. In addition to the primary aims of execution, analyses, and publication of the data, we will also plan for an orderly “closeout” of the NASH CRN in close conjunction with the Data Coordinating Center and the other clinical sites. We remain the highest enrolling site in the VEDS trial and will continue with the ongoing studies with the aim of supporting the entire network in order to achieve completion in the limited time frame. The VEDS trial will lay the foundation for future pivotal studies for NASH. Our recruitment and retention in both the database and VEDS trial have exceeded targets that will help with the timely completion of the studies. Additional important components include informing patients of the results of VEDS as well as a phased transition of patients in the database to clinical care only with the proviso that future studies on NAFLD/NASH may provide additional opportunities for participation in clinical studies. We ...