FSP1 reprograms hepatic lipid metabolism via SIRT1-mediated KU70 deacetylation: an LDLR-bypass atheroprotection

Here we reported that hepatic FSP1 activates SIRT1, driving KU70 deacetylation that creates a YAP-trapping complex-a previously unrecognized molecular switch. This switch sequesters YAP from TEAD4 and silences ANGPTL3 and confers atheroprotection-without touching LDLR.

Furthermore, AAV8-mediated hepatocyte-specific human FSP1 overexpression robustly lowered plasma lipid levels and conferred a protective effect against atherosclerosis in LDLR−/− mice. Notably, analysis of liver data from patients with dyslipidaemia revealed an inverse FSP1-ANGPTL3 correlation. Therefore, our findings redefined FSP1 as a lipid metabolic regulator and uncover a druggable Sirt1-Ku70-YAP cascade for LDLR-bypass lipid lowering.