Therapeutic potential of palmitoleic acid in non-alcoholic fatty liver disease: Targeting ferroptosis and lipid metabolism disorders

Background: Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome associated with obesity and type 2 diabetes mellitus. Currently, there are no effective drugs to treat NAFLD. Palmitoleic acid (PA) has demonstrated therapeutic potential in managing various metabolic diseases and inflammation. Although ferroptosis is known to play a critical role in the NAFLD development, it remains unclear whether PA can alleviate NAFLD by inhibiting ferroptosis. Methods: Thirty C57BL/6 mice were divided into three groups: standard diet, high-fat diet (HFD), and HFD with PA. The experiment lasted 16 weeks. Results: PA alleviated liver injury, hepatitis, and dyslipidemia in HFD-induced NAFLD mice. It improved insulin resistance, downregulated genes and proteins related to fat synthesis, and upregulated genes and proteins linked to lipolysis and fat oxidation. Mechanistically, bioinformatics enrichment revealed the involvement of ferroptosis in NAFLD. PA mitigated oxidative stress and reduced liver iron content in NAFLD. It downregulated acyl-CoA synthetase long-chain family member 4 (ACSL4) expression while upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression, thereby inhibiting ferroptosis. Conclusion: PA exerts a protective effect against liver lipotoxicity by inhibiting lipid metabolism-mediated ferroptosis. These findings provide new insights into preventive and therapeutic strategies for the pathological processes of NAFLD.