Metabolic (dysfunction) associated fatty liver disease (MAFLD) is now one of the most important risk factors for hepatocellular cancer (HCC) in the U.S. Currently, no liver-specific therapies are approved for individuals with MAFLD. Therapy that may block hepatocarcinogenesis – i.e., chemoprevention – is the only practical solution to stem the rising tide of MAFLD-related HCC. In this context, three classes of medications (statins, metformin, and glitazones) hold substantial promise because they act on different metabolic and/or stress-response pathways important in MAFLD-related hepatocarcinogenesis, are commonly used to treat metabolic disorders, and widely available. To our knowledge, no study has examined HCC chemoprevention in MAFLD. There is also limited information about potential harms of these drugs, especially liver related adverse events (AEs) which may be common in persons with MAFLD. The benefits and harms of chemoprevention are likely different in different subgroups. Our study will evaluate the benefits and harms of HCC chemoprevention with these three promising therapies in individuals with MAFLD. To do so, we will use, expand and extend a previously assembled, well-characterized national cohort of MAFLD patients with extensive longitudinal clinical, pharmacy, and laboratory data linked to detailed information from cancer registry, death registry and clinician notes. Using this cohort, and as part of preliminary work, we showed a strong association between MAFLD and HCC and reported an additive effect of metabolic traits on HCC risk. For Aim 1 (benefits of chemoprevention), we will perform a series of carefully designed studies to evaluate the chemopreventive effects of statins (vs. no statins), metformin (vs. no metformin) and pioglitazone (vs. no pioglitazone) in reducing risk of incident HCC. We will also assess the heterogeneity of chemopreventive effects, with specific focus on MAFLD patients with and without cirrhosis, those with varying severity of co-existing metabolic traits, and perform dose-duration analyses to guide tailored chemoprevention. For Aim 2 (harms of chemoprevention), we will use innovations in machine learning followed by manual review of medical charts to conduct a comprehensive comparative evaluation of potential drug-related AEs among patients included in Aim 1 emulated trials. Studies show that genetic factors contribute to differences in response to cancer chemoprevention. In Aim 3 (genetic determinants of benefits), we will use data from an ongoing prospective cohort of patients with MAFLD-cirrhosis to examine few suspected genetic markers that may modify the chemopreventive effects of metformin and/or statins in individuals with MAFLD-cirrhosis. Our research is significant because it will inform guidelines about who, when and how to recommend chemoprevention in patients with MAFLD. Besides elucidating a potential chemopreventive effect in the general MAFLD population, our emphasis on personalized che...