Objective To evaluate and compare the metabolic and hepatic multi-omics responses of mice to a high-fat diet (HFD) and a high-fat/high-fructose diet (HFHFD), and to preliminarily identify shared as well as diet-specific alterations at both the pathway and candidate molecular levels, thereby providing further insight into Metabolic dysfunction–associated steatotic liver disease-associated metabolic remodeling Methods Twenty-one male C57BL/6J mice were randomly divided into three groups:a standard diet, HFD, or HFHFD group (n = 7 per group) and were fed for 8 weeks. Systemic metabolic phenotypes were assessed, including changes in body mass, glucose metabolism, and lipid profiles. Hepatic steatosis and liver injury were evaluated by measuring hepatic triglyceride content, serum ALT/AST levels, and conducting histological analyses. Integrated hepatic transcriptomic and proteomic analyses were performed, with key molecules validated by qRT-PCR..