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Cepharanthine triggers ferroptosis through inhibition of NRF2 for robust ER stress against lung cancer. | LitMetric

Cepharanthine triggers ferroptosis through inhibition of NRF2 for robust ER stress against lung cancer.

Eur J Pharmacol

Department of Pulmonary and Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Renmin Road No. 30, Shiyan, Hubei, 442000, China. Electronic address:

Published: September 2024

AI Article Synopsis

  • Severe endoplasmic reticulum (ER) stress triggers apoptosis in lung cancer, and the study investigates how Cepharanthine (CEP) promotes this process.
  • RNA-sequence analysis revealed that CEP affects gene expression related to ferroptosis and targets NRF2, a key protein in cellular stress response.
  • Experiments showed that CEP induces significant ER stress and ferroptosis in lung cancer cells, leading to increased apoptosis and reduced cancer stemness, highlighting its potential as an effective cancer treatment.

Article Abstract

Background: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer.

Methods: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors.

Results: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, β-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis.

Conclusion: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.

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Source
http://dx.doi.org/10.1016/j.ejphar.2024.176839DOI Listing

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