Spermidine alleviates copper-induced oxidative stress, inflammation and cuproptosis in the liver

Copper exposure poses potential detrimental effects on both public and ecosystem health. Spermidine, an antioxidant, has shown promise in reducing oxidative stress and inflammation within the liver. However, its specific role in mitigating copper-induced hepatic cuproptosis and disturbances in copper metabolism remains unexplored. Consequently, this research aims to investigate to examine the impact of spermidine on hepatic cuproptosis and the related disturbances in copper metabolism. In the study, we established a model of copper-induced liver toxicity by feeding C57BL/6 mice a high-copper diet for three months. Histopathological and biochemical analyses revealed that copper exposure induced hepatic inflammatory cell infiltration, hepatocyte degeneration, elevated levels of MDA, ROS, and Cu2+ accumulation in the liver, and increased ALT and AST activities in serum (p < .05). Regarding inflammation, copper exposure significantly increased serum levels of IL-1 beta, IL-6, and TNF-alpha (p < .05), upregulated TNF-alpha and IFN-gamma expression, and downregulated IL-10 expression in the liver (p < .05). Meanwhile, copper exposure inhibited the expression of copper metabolism and Fe-S cluster-related proteins (p < .05). Exogenous spermidine administration effectively reduced ROS, MDA, and Cu2+ accumulation in the liver, while also decreasing ALT and AST activites, IL-1 beta, IL-6, and TNF-alpha levels in the serum (p < .05), and downregulated TNF-alpha and IFN-gamma expression (p < .001). Additionally, spermidine combined with CuSO4 treatment significantly promotes the expression of copper metabolism and Fe-S cluster-related proteins, compared to the CuSO4 group (p < .05). In summary, spermidine reduces Cu2+ accumulation in the liver, alleviates hepatic cuproptosis, oxidative damage, and inflammation, and exerts a protective effect on the liver.