Aloesin activates Nrf2 signaling to attenuate obesity-associated oxidative stress and hepatic steatosis in high-fat diet-fed rats.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder characterized by hepatic steatosis, oxidative stress, and chronic inflammation. With limited therapeutic options available, there is growing interest in safe bioactive compounds that target underlying mechanisms. Aloesin, a chromone isolated from Aloe vera, possesses potent antioxidants and hypoglycemic properties; however, its protective effect against NAFLD has not been previously examined. This study investigated the hepatoprotective potential of aloesin in rats with high-fat diet (HFD)-induced NAFLD, focusing on the role of Nrf2 signaling. Adult male Wistar rats were divided into seven groups (n = 8/group): control, control + aloesin (200 mg/kg), HFD alone, HFD + aloesin (50, 100, or 200 mg/kg), and HFD + aloesin (200 mg/kg) + brusatol (0.2 mg/kg, i.p.). Treatments were administered twice weekly for 12 weeks. Aloesin dose-dependently improved metabolic and hepatic profiles, reducing body and liver weights, fasting glucose, insulin, HbA1c, HOMA-IR, and serum and hepatic levels of triglycerides, cholesterol, and LDL-c, with 200 mg/kg showing the greatest efficacy. It increased hepatic glucokinase and decreased G6Pase activity. Liver histology revealed restored architecture and reduced inflammation. Serum ALT, AST, and GGT were significantly lowered. Molecular analyses showed increased nuclear Nrf2 and antioxidant markers (GSH, SOD, HO-1), with suppressed NF-κB, TNF-α, IL-6, Bax, and caspase-3, and upregulated Bcl-2. Aloesin also modulated lipid metabolism by decreasing SREBP1 and increasing PPARα expression. These effects were reversed by brusatol, confirming Nrf2 pathway involvement. In conclusion, aloesin confers potent Nrf2-mediated protection against NAFLD, with 200 mg/kg as the optimal therapeutic dose.