Iron overload activates NF-κB-driven hepatic inflammation in suckling rats

Iron is crucial for infant development but excessive iron intake may adversely affect liver. The neonatal period is critical for liver development and immune system maturation, during which the liver is particularly vulnerable to iron overload. The mechanism of high iron intake affecting liver health in infants remains unclear. This study aims to investigate the effects of high iron supplementation on liver structure and functions in infants. Suckling rats with different iron supplementation (10, 50, and 100 mg Fe/kg body weight) were utilized to analyze the impact of high iron on hepatic structure, intermediary metabolism, and immune responses. Results showed that there was obvious inflammatory cell infiltration in the liver of rat pups with high iron supplementation (50 and 100 mg/kg), with increased ALT and AST. Notably, high doses of iron activated the immune system by promoting M1 polarization of macrophages, leading to inflammatory response with increased IL-6, TNF-α, IL-1β, and CCL2 mRNA and decreased IL-10 mRNA. Furthermore, enhanced phosphorylation of p65 in suckling rats which is key for activating the NF-κB signaling pathway was observed. Also, excessive iron induced oxidative stress in the liver, leading to activation of the Nrf2/HO-1 antioxidant pathway as a compensatory response, with upregulated Nrf2 and HO-1 mRNA and decreased Keap-1 mRNA. The antioxidant activation was insufficient to counteract iron-induced inflammatory signaling. Overall, this study suggested that excessive iron intake during suckling activated the NF-κB pathway, thereby promoting M1-like macrophages polarization, generating inflammatory response, leading to impaired liver. These findings reveal the intrinsic mechanisms of iron overload-induced liver damage during suckling, providing an important theoretical basis for the treatment of diseases caused by excessive iron in infants and young children.