Fatty Acid Synthase–Suppressor Screening Identifies Sorting Nexin 8 as a Therapeutic Target for NAFLD

Background and Aims NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration–approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate‐limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown. Methods and Results Through a systematic interactomics analysis of FASN‐complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28–FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro , whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8 ‐knockout mice compared to wild‐type controls. Consistently, hepatocyte‐specific overexpression of Snx8 in vivo markedly suppressed high‐fat, high‐cholesterol diet (HFHC)–induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression. Conclusions These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8–FASN axis is a promising strategy for NAFLD prevention and treatment.