Hepatocelluar carcinoma (HCC) is the fastest growing cause of cancer deaths among Americans. In the past decade, there has been an epidemic increase in metabolic (dysfunction) associated fatty liver disease (MAFLD)-related cirrhosis and HCC. MAFLD is estimated to affect 1 billion individuals globally and is projected to become the leading cause of HCC in the next 2 decades. There is an urgent need to develop effective strategies to reduce HCC burden in the growing MAFLD population. The overall goal of the Program Project (PP) is to reduce the burden of HCCrelated mortality through better understanding of contemporary risk factors (e.g., metabolic traits and biomarkers) and protective factors (e.g., chemoprevention, HCC surveillance) of HCC related to MAFLD. We propose three highly integrated studies. Central to this PP is leveraging and expanding our multicity, prospective cohort of persons with MAFLD-related cirrhosis, the Texas HCCC Consortium (THCCC) Cohort, which will serve as a resource for the proposed studies. The goal of Project 1 is to develop HCC risk stratification models based on phenotypic, metabolic, radiomic and genetic markers of metabolic dysfunction among patients with cirrhosis. We propose the analysis of data and biospecimens from the prospective THCCC cohort of >5000 patients with cirrhosis (and 350-400 incident HCC) to develop a suite of risk score algorithms) for predicting the risk of HCC among patients with cirrhosis. The goal of Project 2 is to evaluate the chemopreventive effects and potential harms of metformin, statins or glitazones in reducing the risk of HCC in individuals with MAFLD. We propose a retrospective cohort study using national VA datasets of >580,000 patients with MAFLD. We will also examine the effect of genetic markers on the chemopreventive effects of these medications in patients with MAFLD cirrhosis in THCCC. The goal of Project 3 is to examine comparative cost-effectiveness of prevention strategies in MAFLD. We will develop a mathematical simulation model and perform comparative analyses of benefits vs. harms of chemoprevention and HCC surveillance in individuals with MAFLD, and of using precision surveillance/chemoprevention using HCC risk stratification We propose a Data & Analysis Core to support data management, data harmonization, statistical analyses and web-based tools; a Biospecimen and Biomarker Development Core to support collection, processing, transport and storage of serum and DNA samples from THCCC cohort; and conduct biomarker assays for the projects, and an Administrative Core to provide management, communication and coordination among projects, Cores, investigators and staff.