The Modulatory Effect of Liraglutide on the Expression of GPX4, HO-1 and SLC7A11 Signaling Pathway in Obese Rats

Background: Obesity, a multifaceted metabolic condition, is associated with oxidative stress and disrupted redox homeostasis, leading to ferroptosis and metabolic dysfunction. Liraglutide, a well-known glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of obesity. This study aimed to examine the modulatory effects of liraglutide on oxidative stress and ferroptosis-related indicators in obese rats induced by high-fat diet (HFD). Methods: Thirty-five male Wistar rats were randomly divided into five groups: a control group, an HFD-induced obesity group, and three liraglutide treatment groups (100, 200, and 400 μg/kg/day). Following a 4-week induction of HFD, liraglutide was administered subcutaneously for 28 days. Redox and ferroptosis changes were assessed by measuring serum iron, TfR-1, malondialdehyde (MDA), and superoxide dismutase (SOD), along with gene expression of SLC7A11 and the immunohistochemical expression of heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (GPX4) in hepatic tissues. Results: HFD-induced obesity significantly reduced the expression of antioxidant and ferroptosis-regulatory markers. Liraglutide treatment, particularly at high doses, significantly reversed these effects by upregulating SLC7A11 gene expression and enhancing HO-1, and GPX4 protein expression in a dose-dependent manner. Conclusion: These findings suggest that liraglutide restores antioxidant capacity and inhibits ferroptosis through activation of the SLC7A11/HO-1/GPX4 axis. Beyond its metabolic benefits, liraglutide exerted cytoprotective effects, highlighting its potential therapeutic role in obesity-associated oxidative stress and ferroptosis injury.