Dehydrocostus lactone attenuates hepatic steatosis by regulating fatty acid oxidation and lipid metabolism: integrated transcriptomic and metabolomic analysis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and atherosclerosis (AS) are closely linked cardiometabolic disorders characterized by dysregulated lipid metabolism, inflammation, and insulin resistance. This study investigated the effects of dehydrocostus lactone (DHL) on hepatic lipid metabolism and histopathology in a preclinical mouse model of concurrent MAFLD and AS, and elucidated its underlying molecular mechanisms. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat diet (HFD) for 10 weeks and treated with low, medium, or high doses of DHL, or simvastatin as a positive control. Liver morphology, histology (H&E, Masson's trichrome, Oil Red O staining), and biochemical markers of total cholesterol (TC), triglyceride (TG), Aspartate aminotransferase, Alanine aminotransferase were assessed. Integrated transcriptomic and metabolomic analyses of liver tissues were performed to identify DHL-regulated signaling pathways. DHL markedly reduced hepatic lipid accumulation and collagen deposition compared with HFD controls, as evidenced by decreased Oil Red O-positive areas and reduced TC and TG levels. DHL improved liver fibrosis and normalized serum transaminases without significantly affecting body weight. Mechanistically, DHL upregulated peroxisome proliferator-activated receptor alpha (PPAR-α) and its downstream target carnitine palmitoyl-transferase 1β (CPT1-β), enhancing fatty acid β-oxidation, while suppressing fatty acid binding protein 5 (FABP5) to reduce intracellular lipid retention. Metabolomic profiling revealed restoration of carnitine pools and vitamin A levels, indicating improved mitochondrial fatty acid transport and hepatic function. DHL exerts multi-targeted protective effects against HFD-induced hepatic steatosis in ApoE-/- mice by coordinately regulating lipid oxidation, uptake, and metabolic pathways, which suggests that DHL represents a promising therapeutic candidate for the concurrent management of MAFLD and AS.