TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase

Nonalcoholic liver disease (NAFLD) encompasses a disease continuum from simple steatosis, to non-alcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NALFD, identification of potential therapeutic targets is clinically important. Here, we demonstrated that TRIM56 protein abundance is markedly downregulated in the livers of individuals with NAFLD and mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactomic and transcriptomic profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified lipogenesis factor FASN as a direct binding partner of TRIM56. TRIM56 directly interacts with FASN and triggers its K48-linked ubiquitination-dependent degradation. Finally, by using AI-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) which potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with optimal safety, tolerability and pharmacokinetic profile. Our findings provide the proof-of-concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.