Dual protection by naringin and dexrazoxane against iron-induced erythrocyte damage: Exploring their synergistic regulation of ferroptosis and eryptosis.

Iron cellular accumulation is linked to ferroptosis, which induces cell injury. Conventional iron chelators often elicit side effects and encourage the exploration of naringin (NAR) as a potential protective agent against ferroptosis. Erythrocytes are a simple cellular model for exploring the beneficial effects of bioactive compounds. This study aims to investigate the protective effects of NAR against ferrous sulfate (FeSO4) induced ferroptosis. FeSO4 and hydrogen peroxide were applied to erythrocytes to induce ferroptosis either in the presence or absence of NAR, dexrazoxane (DEX), or their combination and compared to control cells. Key indicators of ferroptosis, including reactive oxygen species (ROS) production, GPX4 activity, glutathione (GSH) levels, malondialdehyde (MDA) levels, GPX4, GRD, and erythrocyte cytolysis, and eryptosis were analyzed using spectrophotometric and flow cytometric methods. Molecular docking studies with AutoDock Vina assessed the interactions between DEX, NAR, GPX4, GRD, HO-1, GST, SDH, AChE, and NOS. The present results displayed that both DEX and NAR significantly mitigates FeSO4-induced ROS production and lipid peroxidation while preserving GSH levels and enhancing GPX and GRD activities compared to the FeSO4-treated group. DEX and NAR also effectively prevented iron-induced erythrocyte cytolysis and eryptosis. The DEX and NAR combination produced pronounced effect of the measured parameters compared to other groups. Docking analysis indicated stronger binding affinities of NAR to GPX4, GRD, HO-1, GST, SDH, AChE, and NOS compared to DEX, suggesting NAR may be a more effective modulator. These findings concluded that NAR is a potential alternative to traditional DEX as iron chelators. Moreover, NAR is a promising therapy for disorders connected with iron overloading.