Project Summary Metabolic dysfunction associated steatotic liver disease (MASLD), previously referred to as nonalcoholic fatty liver disease, or NAFLD, affects over 30% of the US population and is a leading cause of cirrhosis, liver cancer, and need for liver transplantation. The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), established in 2002, has focused on characterizing the natural history of the different phenotypes of MASLD, evaluating novel therapies to treat the condition, and conducting translational studies using a rich repository of clinical, pathologic, imaging, and -omics data to advance knowledge. Since the last funding cycle, the NASH CRN adult or pediatric clinical centers have enrolled 1575 participants into a longitudinal database, including 617 newly enrolled individuals and undertaken two clinical trials: the Losartan for Pediatric NAFLD (STOP-NAFLD) trial which was terminated early based on DSMB recommendation and the Vitamin E Dose Ranging Study (VEDS), initiated in 2021, which is 50% enrolled. During the current funding period, 219,404 total samples (serum, plasma, liver tissue, DNA and cDNA), including samples for ~1,220 new patients, were added in the NIDDK Biorepository, and 49,957 samples withdrawn for translational research using the Ancillary Studies mechanism. The objectives of the NASH CRN during the final funding period are (a) to successfully complete the observational longitudinal study of NAFLD in adults and children (NAFLD Database study, (b) complete the enrollment and follow-up of the VEDS clinical trial (N=250) and to conduct new translational studies based on the clinical and archived biospecimens from previous funding These studies may focus on (but not limited to) natural history of NAFLD and NASH in children and adults, non-invasive assessment of disease severity (e.g., proteomics, lipodimics, clinical prediction rules) and disease pathogenesis (cytokine analyses, genome-wide association studies, tissue proteomics). Site-specific studies include measurement of individual- and neighborhood-level social and structural determinants of health (SSDOH) including geospatial variables, to determine their influence on MAFLD development and progression and to evaluate whether the social and structural environment, as measured by the social deprivation index, modifies the risk of germline genetic variants (PNPLA3 and others) on disease severity and progression. Collectively, these studies are and anticipated to address key knowledge gaps in MASLD diagnosis, treatment and prognosis.