SIRT1-mediated FABP4 destabilization attenuates fibrosis and ferroptosis in non-alcoholic fatty liver disease.

OBJECTIVE: This study aims to unveil the role and mechanism of histone deacetylase SIRT1 in modulating fatty acid binding protein 4 (FABP4) stability and its impact on hepatic fibrosis and ferroptosis in non-alcoholic fatty liver disease (NAFLD). METHODS: A murine NAFLD fibrosis model was induced by a Western diet combined with CCl(4) injection. Mice received adenoviruses carrying oe-SIRT1 or sh-FABP4 three days before modeling. In vitro, NCTC 1469 hepatocytes were exposed to palmitic acid (PA) and transfected with oe-SIRT1 or oe-FABP4. Histopathology was assessed by HE, Masson, and Sirius red staining, and α-SMA by immunohistochemistry. Biochemical assays and molecular analyses measured liver injury markers, ferroptosis-related proteins, oxidative stress indices, and SIRT1/FABP4 expression. Cell viability, death, and lipid deposition were evaluated by CCK-8, LDH release, and Oil Red O staining. Co-IP and CHX chase assays examined SIRT1–FABP4 interaction, acetylation, and protein stability. RESULTS: NAFLD mice showed decreased SIRT1 and increased FABP4, with lipid degeneration, collagen deposition, α-SMA upregulation, and aggravated ferroptosis. Either SIRT1 overexpression or FABP4 knockdown alleviated inflammation, fibrosis, and ferroptosis in vivo. In PA-treated hepatocytes, cell viability declined, LDH release and lipid deposition increased, AST/ALT rose, ferroptosis intensified, SIRT1 was suppressed, and FABP4 was upregulated. Enhancing SIRT1 reduced FABP4 expression, attenuated lipid accumulation, and limited ferroptosis. Mechanistically, SIRT1 interacted with FABP4 to decrease its acetylation, thereby lowering FABP4 stability. FABP4 overexpression partially reversed the protective effect of SIRT1, promoting ferroptosis and lipid deposition. CONCLUSION: SIRT1 reduces FABP4 acetylation and stability, thereby suppressing ferroptosis and hepatic fibrosis in NAFLD. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10238-025-02029-8.