Network pharmacology combined with the experiments reveals ferroptosis-related targets of quercetin against DON-induced liver injury.

Deoxynivalenol (DON) is a mycotoxin that severely contaminates agri-food products and causes liver injury. Quercetin (Que) has anti-ferroptosis and hepatoprotective effects. This study employed a network pharmacology approach to investigate ferroptosis-associated targets underlying Que's mitigation of DON-induced liver injury, with experimental validation of its hepatoprotective mechanisms. We identified five ferroptosis regulatory targets of Que associated with liver injury: GPX4, HMOX1, SLC7A11, and TFRC. Enrichment analysis revealed key signaling pathways modulated by Que in liver injury: ferroptosis. The results showed that DON significantly decreased the levels of SLC7A11 and GPX4 and increased the levels of TFRC in liver tissue. DON decreased GSH level and GSH-Px activity, and increased MDA and iron levels, resulting in structural and functional damage to hepatocyte mitochondria and liver tissue. All of these DON-induced adverse liver changes were reversed by Que treatment, thereby improving the growth performance of mice. In vitro, DON decreased GPX4, SLC7A11, GCLC, NQO1, and Nrf2 expression; promoted TFRC expression and MDA, 4-HNE, and total ROS production; accelerated GSH depletion; and enhanced lipid ROS accumulation and Fe(II) overload, leading to ferroptosis. Que pretreatment reversed these changes and alleviated DON-induced ferroptosis, thereby increasing cell viability and cell growth. In addition, Que decreased erastin and RSL3-induced lipid ROS level. Altogether, Que attenuated DON-induced liver injury by activating the SLC7A11/GSH/GPX4 signalling pathway, and thereby inhibiting hepatic ferroptosis. This study indicated that Que has a positive impact on liver health in toxin pollution.