Copper deficiency aggravates oxidative stress, inflammation, and liver damage induced by a high-fat diet in a mouse model.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and is strongly associated with metabolic syndrome. Copper, an essential cofactor for enzymes involved in redox regulation and lipid metabolism, is frequently diminished in MASLD patients. Copper deficiency may exacerbate oxidative stress, inflammation, and hepatocellular damage. The aim of this study was to investigate the impact of dietary copper deficiency on oxidative stress, inflammatory response, and histopathological alterations in mice fed a high-fat diet. Male C57BL/6 J mice (n = 32) were assigned to four groups: control diet (CD), copper-deficient control diet (CD-Cu), high-fat diet (HFD), and copper-deficient high-fat diet (HFD-Cu) for 12 weeks. Biochemical, histological, and molecular parameters were evaluated. Mice in the HFD-Cu group exhibited significantly greater dyslipidemia, elevated transaminases, increased hepatic lipid accumulation, enhanced oxidative stress (reduced SOD1 activity, increased TBARS, protein carbonyls, and GSSG), and higher inflammatory cytokine levels (TNF-α, IL-1β) compared to HFD alone. Histological analysis confirmed more severe macrovesicular steatosis and inflammation in HFD-Cu mice. In conclusion, copper deficiency potentiates the deleterious effects of a high-fat diet, aggravating oxidative stress, inflammation, and hepatic injury. These results highlight the critical role of copper in liver homeostasis and its potential involvement in MASLD progression.