Network pharmacology-based identification of the key mechanism of quercetin acting on hemochromatosis

Abstract Hemochromatosis is an iron overload disease, which lacks nutritional intervention strategies. This study explored the protective effect of quercetin on hemochromatosis and its possible mechanism through network pharmacology. We used Online Mendelian Inheritance in Man to screen the disease targets of hemochromatosis, and further constructed a potential protein interaction network through STITCH. The above-mentioned targets revealed by Gene enrichment analysis have played a significant role in ferroptosis, mineral absorption, basal cell carcinoma, and related signal pathways. Besides, the drug likeness of quercetin obtained by Comparative Toxicogenomics Database was evaluated by Traditional Chinese Medicine Systems Pharmacology, and potential drug targets identified by PharmMapper and similar compounds identified by PubChem were selected for further research. Moreover, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed the relationship between quercetin and glycosylation. Furthermore, we performed experiments to verify that the protective effect of quercetin on iron overload cells is to inhibit the production of reactive oxygen species, limit intracellular iron, and degrade glycosaminoglycans. Finally, iron-induced intracellular iron overload caused ferroptosis, and quercetin and fisetin were potential ferroptosis inhibitors. In conclusion, our study revealed the correlation between hemochromatosis and ferroptosis, provided the relationship between the target of quercetin and glycosylation, and verified that quercetin and its similar compounds interfere with iron overload related disease. Our research may provide novel insights for quercetin and its structurally similar compounds as a potential nutritional supplement for iron overload related diseases.