2498-P: Miglitol Ameliorates the Progression of High-Fat Diet–Induced Metabolic Dysfunction–Associated Steatotic Liver Disease in Mice by Inhibiting Ferroptosis

Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common complications of type 2 diabetes. Disease progression is closely linked to oxidative stress and ferroptosis, a novel form of regulated cell death. The effect and mechanism of miglitol, a classical anti-diabetic drug, on MASLD remain unclear. This study aimed to investigate the potential effect of miglitol on MASLD, thereby proposing a new therapeutic strategy for MASLD. Methods: Male C57BL/6N mice were randomly divided into six groups: control, high-fat diet (HFD), HFD with low-, medium-, high-dose miglitol, and HFD with acarbose. After 8 weeks of intervention, metabolic phenotypes and liver pathology were assessed. An in vitro model was established in AML-12 hepatocytes using palmitic acid/oleic acid (PA/OA), with or without miglitol co-treatment. Proteomics, biochemical assays, immunofluorescence, and Western blotting were employed to analyze its effects on lipid metabolism and ferroptosis. Results: In animal studies, miglitol significantly ameliorated HFD-induced weight gain, liver weight, and hepatic lipid accumulation. In PA/OA induced cell models, proteomic profiling revealed that miglitol potently modulated pathways related to lipid metabolism and ferroptosis. Immunofluorescence demonstrated that miglitol markedly attenuated intracellular lipid peroxide accumulation and labile iron pool. Western blotting further confirmed that miglitol counteracted the HFD-induced and PA/OA-induced upregulation of the pro-ferroptotic marker 4-HNE and restored the expression of key anti-ferroptotic proteins, GPX4 and FTH1. Conclusion: This study is the first to demonstrate that miglitol alleviates MASLD progression in vitro and in vivo by inhibiting ferroptosis, improving lipid metabolism, and reducing oxidative stress. These findings provide robust preclinical evidence for its repositioning as a potential therapeutic agent for MASLD. Disclosure J. Zhou: None. J. Liu: None. X. Xiao: None.