Copper-induced duodenal injury: Unveiling the dual role of cuproptosis and ferroptosis via the FDX1/GPX4 axis.

Copper (Cu) is an essential trace element for humans but also a common environmental pollutant. Excessive intake can lead to poisoning, yet the mechanisms by which it causes duodenal injury remain unclear. To investigate the involvement of cuproptosis and ferroptosis in this process, we conducted an experiment using 72 one-day-old Peking ducks, randomly assigned to four groups according to dietary Cu levels: control, 100 mg/kg Cu, 200 mg/kg Cu, and 400 mg/kg Cu. Our findings demonstrate that excessive Cu exposure markedly reduced body weight, caused pathological damage to the duodenum, and triggered oxidative stress. Mechanistically, Cu accumulation in tissues suppressed the expression of ATP7A, PDHB, and FDX1, while upregulating DLAT, Lip-DLAT and HSP70, thereby promoting cuproptosis. Subsequently, cuproptosis acts through the FDX1/GPX4 axis to elevate the expression of TfR1 and increase intracellular iron/ferrous ion levels, while reducing the expression of GPX4, SLC7A11, Cyt C, ISCU, FTH-1, and NAF1. These collective alterations ultimately induce ferroptosis. These changes exhibit a dose-dependent relationship with Cu. In summary, our study suggests that excessive Cu disrupts copper homeostasis, initiates cuproptosis, and perturbs iron metabolism through FDX1- and GPX4-mediated regulation, thereby triggering ferroptosis. These results provide new mechanistic insights into Cu-induced cytotoxicity.