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

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

  • Free Radic Biol Med. 2024 Jan 6:S0891-5849(24)00002-9. doi: 10.1016/j.freeradbiomed.2024.01.002.
Lixian Ding 1,  Shuwei Dang 2,  Mingjun Sun 3,  Dazhi Zhou 4,  Yanyan Sun 5,  Encheng Li 6,  Shuqi Peng 7,  Jinxing Li 8,  Guodong Li 9
Affiliations

Affiliations

  • 1 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: dinglixian@hrbmu.edu.cn.
  • 2 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: dangshuwei@hrbmu.edu.cn.
  • 3 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: 2020022009@hrbmu.edu.cn.
  • 4 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: a18253802926@163.com.
  • 5 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: 601589@hrbmu.edu.cn.
  • 6 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: lienchengdyx@163.com.
  • 7 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: 2021022095@hrbmu.edu.cn.
  • 8 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Department of General Surgery, The Fourth Hospital of Harbin, Harbin, 150001, China. Electronic address: 2020021997@hrbmu.edu.cn.
  • 9 Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China; Bio-Bank of Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. Electronic address: liguodong@ems.hrbmu.edu.cn.
PMID: 38190923 DOI: 10.1016/j.freeradbiomed.2024.01.002
Abstract

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.

Keywords

Ferroptosis; Gastric cancer; NRF2; Quercetin; SLC1A5; p-DRP1.

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