Quercetin induces ferroptosis in gastric cancer cells by targeting SLC1A5 and regulating the p-Camk2/p-DRP1 and NRF2/GPX4 Axes

• Published in: Free radical biology & medicine Vol. 213; pp. 150 - 163
• Main Authors: Ding, Lixian, Dang, Shuwei, Sun, Mingjun, Zhou, Dazhi, Sun, Yanyan, Li, Encheng, Peng, Shuqi, Li, Jinxing, Li, Guodong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2024
• Subjects: Amino Acid Transport System ASC; Antioxidants; Ferroptosis; Ferroptosis - genetics; Gastric cancer; Humans; Iron; Minor Histocompatibility Antigens; Molecular Docking Simulation; NF-E2-Related Factor 2 - genetics; NRF2; p-DRP1; Quercetin; Quercetin - pharmacology; Reactive Oxygen Species; SLC1A5; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Ferroptosis; SLC1A5; NRF2; p-DRP1; Gastric cancer; Quercetin
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.01.002

Quercetin (Quer) is a natural flavonoid known for its inhibitory effects against various cancers. However, the mechanism by which Quer inhibits gastric cancer (GC) has not yet been fully elucidated. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. Through flow cytometry and other detection methods, we found that Quer elevated lipid peroxidation levels in GC cells. Transmission electron microscopy confirmed an increase in ferroptosis in Quer-induced GC. We demonstrated that Quer inhibits SLC1A5 expression. Molecular docking revealed Quer's binding to SLC1A5 at SER-343, SER-345, ILE-423, and THR-460 residues. Using immunofluorescence and other experiments, we found that Quer altered the intracellular ROS levels, antioxidant system protein expression levels, and iron content. Mechanistically, Quer binds to SLC1A5, inhibiting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in decreased xCT/GPX4 expression. Quer/SLC1A5 signaling activated p-Camk2, leading to upregulated p-DRP1 and enhanced ROS release. Additionally, Quer increased the intracellular iron content by inhibiting SLC1A5. These three changes collectively led to ferroptosis in GC cells. In conclusion, Quer targets SLC1A5 in GC cells, inhibiting the NRF2/xCT pathway, activating the p-Camk2/p-DRP1 pathway, and accelerating iron deposition. Ultimately, Quer promotes ferroptosis in GC cells, inhibiting GC progression. Overall, our study reveals that Quer can potentially impede GC progression by targeting SLC1A5, offering novel therapeutic avenues through the modulation of ferroptosis and iron homeostasis. [Display omitted] •Quercetin elevates ferroptosis level in GC cells, inhibiting GC progression.•We identified SLC1A5 as a target of quercetin in GC and predicted poteintial sites.•Quercetin promotes the NRF2/xCT pathway by targeting SLC1A5 to induce ferroptosis.•Quercetin activates the p-Camk2/p-DRP1 axis via SLC1A5 to promote ferroptosis.•Inhibition of SLC1A5 by quercetin caused intracellular iron deposition.