Introduction and Objective: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver disease linked to obesity and metabolic disorders. Caloric restriction (CR) and intermittent fasting (IF) improve metabolic health, but their effects on MAFLD and underlying mechanisms are unclear. This study compared CR and IF regimens in MAFLD models and explored the role of glutathione S-transferase Mu3 (GSTM3) in mediating these effects.Methods: MAFLD was induced in db/db and HFD/STZ-treated C57 mice. Animals underwent ad libitum feeding, CR, or EODF for 56 days. Metabolic parameters, liver pathology, and mitochondrial function were assessed. Transcriptomics identified GSTM3 as a key target, validated by RT-qPCR, Western blot, and immunofluorescence. CREB1 regulation of GSTM3 was confirmed by ChIP assays. Liver-specific GSTM3 overexpression was evaluated in mouse models.Results: Under matched caloric restriction conditions, both CR and EODF similarly improved body weight, liver lipid deposition, inflammatory levels, and glucose metabolism in MAFLD mice. Both CR and EODF significantly upregulated the expression of GSTM3 in the liver, mediated by the transcription factor CREB1. GSTM3 expression was reduced in MAFLD patients and animal models, while overexpression of GSTM3 significantly alleviated liver lipid accumulation, inflammation, and insulin resistance, improved mitochondrial function, and promoted fatty acid oxidation. Mechanistically, GSTM3 localized to the mitochondria, scavenged reactive oxygen species and lipid peroxides, and protected mitochondrial function.Conclusion: The intensity, rather than the type, of caloric restriction plays a key role in ameliorating MAFLD. CR upregulates GSTM3 expression in a CREB1-dependent manner, enhances mitochondrial function, and promotes fatty acid oxidation, thereby effectively improving the pathological state of MAFLD. GSTM3 may serve as a potential therapeutic target for MAFLD
X. Hong: None. S. Chen: None. J. Lin: None. M. Ren: None. L. Yan: None. W. Wang: None.
National Natural Science Foundationof China (U20A20352), Guangdong Basic and Applied Basic Research Foundation (2023A1515030079)
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