The article explores how the TRIM56 protein helps prevent nonalcoholic fatty liver disease (NAFLD) by promoting the degradation of fatty acid synthase (FASN). Researchers found that TRIM56 levels are significantly reduced in the livers of individuals with NAFLD and in mice fed a high-fat diet. When TRIM56 is removed from hepatocytes, it worsens NAFLD, while increasing TRIM56 levels suppresses it. Through integrative analysis of interactome and transcriptome data, the study identifies FASN as a direct binding partner of TRIM56. TRIM56 interacts with FASN and triggers its K48-linked ubiquitination-dependent degradation. Using artificial intelligence-based virtual screening, the researchers discovered an orally available small-molecule inhibitor of FASN, named FASstatin, which enhances TRIM56-mediated FASN ubiquitination. Administering FASstatin improved NAFLD and NASH pathologies in mice with good safety and tolerability profiles. The study provides evidence that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues for treating NAFLD. The findings highlight the role of TRIM56 in antiviral innate immunity and suggest a potential pharmaceutical intervention strategy for NAFLD by targeting the TRIM56/FASN axis. The research demonstrates that TRIM56 blocks hepatocyte lipid accumulation by interacting with FASN and promoting its degradation. The study also shows that FASN inhibition blocks the effect of TRIM56 ablation on lipid accumulation. The researchers identified FASN as a TRIM56 binding partner and demonstrated that TRIM56 interacts with FASN and promotes its degradation. The study further shows that FASstatin, a small-molecule inhibitor of FASN, enhances TRIM56-FASN interaction and increases TRIM56-driven FASN degradation, thereby ameliorating NAFLD pathologies in mice. The results suggest that targeting the TRIM56/FASN axis may be a promising therapeutic approach for NAFLD. The study also highlights the potential of FASstatin as an orally available and well-tolerated drug for treating NAFLD and NASH.The article explores how the TRIM56 protein helps prevent nonalcoholic fatty liver disease (NAFLD) by promoting the degradation of fatty acid synthase (FASN). Researchers found that TRIM56 levels are significantly reduced in the livers of individuals with NAFLD and in mice fed a high-fat diet. When TRIM56 is removed from hepatocytes, it worsens NAFLD, while increasing TRIM56 levels suppresses it. Through integrative analysis of interactome and transcriptome data, the study identifies FASN as a direct binding partner of TRIM56. TRIM56 interacts with FASN and triggers its K48-linked ubiquitination-dependent degradation. Using artificial intelligence-based virtual screening, the researchers discovered an orally available small-molecule inhibitor of FASN, named FASstatin, which enhances TRIM56-mediated FASN ubiquitination. Administering FASstatin improved NAFLD and NASH pathologies in mice with good safety and tolerability profiles. The study provides evidence that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues for treating NAFLD. The findings highlight the role of TRIM56 in antiviral innate immunity and suggest a potential pharmaceutical intervention strategy for NAFLD by targeting the TRIM56/FASN axis. The research demonstrates that TRIM56 blocks hepatocyte lipid accumulation by interacting with FASN and promoting its degradation. The study also shows that FASN inhibition blocks the effect of TRIM56 ablation on lipid accumulation. The researchers identified FASN as a TRIM56 binding partner and demonstrated that TRIM56 interacts with FASN and promotes its degradation. The study further shows that FASstatin, a small-molecule inhibitor of FASN, enhances TRIM56-FASN interaction and increases TRIM56-driven FASN degradation, thereby ameliorating NAFLD pathologies in mice. The results suggest that targeting the TRIM56/FASN axis may be a promising therapeutic approach for NAFLD. The study also highlights the potential of FASstatin as an orally available and well-tolerated drug for treating NAFLD and NASH.