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Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway

  • Authors:
    • Jie Zhang
    • Shanshan Qi
    • Yanyan Du
    • Honghong Dai
    • Ninghua Liu
  • View Affiliations / Copyright

    Affiliations: Traditional Chinese Medicine Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Department of Oncology, Shijiazhuang Hospital of Traditional Chinese Medicine, Shijiazhuang, Hebei 050000, P.R. China, Clinical Laboratory Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Gynecology and Oncology Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China, Functional Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 57
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    Published online on: March 31, 2025
       https://doi.org/10.3892/or.2025.8890
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Abstract

It has been reported that treatment of patients with non‑small cell lung cancer (NSCLC) with gefitinib increases the risk of QT interval prolongation. Therefore, the present study aimed to investigate whether quercetin could delay gefitinib‑induced cardiomyocyte apoptosis and its underlying mechanism. A total of 32 nude mice were divided into the sham, NSCLC, NSCLC + gefitinib and NSCLC + gefitinib + quercetin groups. Cardiac fibrosis in mouse heart tissues was assessed by Masson's trichrome staining. Additionally, immunohistochemical staining was performed to detect the expression levels of Src homology‑2 domain‑containing protein tyrosine phosphatase (SHP2), X‑box binding protein 1 (XBP‑1), phosphorylated (p)‑stimulator of interferon genes (STING) and Nod‑like receptor protein 3. Bioinformatics analysis was carried auto to predict the association between quercetin and the SHP2/reactive oxygen species (ROS) axis. Furthermore, the effects of adenosine triphosphate (ATP) + gefitinib, SHP2 silencing and H2O2 on ROS levels, as well as on the p‑AMP‑activated protein kinase (AMPK)/XBP‑1/Parkinsonism associated deglycase (DJ‑1) axis, mitochondrial autophagy and apoptosis were assessed via detecting the expression levels of the corresponding proteins in cardiomyocytes by western blot analysis. JC‑1 immunofluorescence was performed to evaluate mitochondrial membrane damage. The results showed that NSCLC could not significantly affect cardiac function. In addition, compared with NSCLC alone, ventricular fibrosis was exacerbated in the NSCLC + gefitinib group. However, treatment with quercetin inhibited gefitinib‑induced ventricular fibrosis, activated the gefitinib‑suppressed SHP2 protein expression and downregulated the gefitinib‑induced XBP‑1 and p‑STING expression. Furthermore, the bioinformatics analysis results predicted that quercetin could interact with SHP2/ROS. The in vitro experiments demonstrated that the expression levels of the ROS‑related proteins, namely NADPH oxidase 4 and XBP‑1/DJ‑1, and those of the mitochondrial autophagy‑ and apoptosis‑related proteins were enhanced, while those of p‑AMPK, were reduced in cardiomyocytes of the NSCLC + ATP + gefitinib group. However, cell treatment with quercetin inhibited ROS production and the expression levels of XBP‑1/DJ‑1 and apoptosis‑related proteins activated by NSCLC + ATP + gefitinib. By contrast, quercetin activated the expression levels of mitochondrial autophagy‑related proteins and those of p‑AMPK. Furthermore, SHP2 silencing and cell treatment with H2O2 could separately inhibit the NSCLC + ATP + gefitinib‑induced expression of mitochondrial autophagy‑related proteins and p‑AMPK, while they could promote ROS production and upregulate XBP‑1/DJ‑1 and apoptosis‑related proteins. In summary, the results of the current study revealed a promising therapeutic approach for addressing cardiac issues caused by gefitinib treatment in patients with NSCLC. Therefore, quercetin could inhibit the gefitinib‑induced NSCLC‑mediated cardiomyocyte apoptosis via regulating the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway through mitochondrial autophagy.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang J, Qi S, Du Y, Dai H and Liu N: Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway. Oncol Rep 53: 57, 2025.
APA
Zhang, J., Qi, S., Du, Y., Dai, H., & Liu, N. (2025). Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway. Oncology Reports, 53, 57. https://doi.org/10.3892/or.2025.8890
MLA
Zhang, J., Qi, S., Du, Y., Dai, H., Liu, N."Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway". Oncology Reports 53.5 (2025): 57.
Chicago
Zhang, J., Qi, S., Du, Y., Dai, H., Liu, N."Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway". Oncology Reports 53, no. 5 (2025): 57. https://doi.org/10.3892/or.2025.8890
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang J, Qi S, Du Y, Dai H and Liu N: Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway. Oncol Rep 53: 57, 2025.
APA
Zhang, J., Qi, S., Du, Y., Dai, H., & Liu, N. (2025). Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway. Oncology Reports, 53, 57. https://doi.org/10.3892/or.2025.8890
MLA
Zhang, J., Qi, S., Du, Y., Dai, H., Liu, N."Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway". Oncology Reports 53.5 (2025): 57.
Chicago
Zhang, J., Qi, S., Du, Y., Dai, H., Liu, N."Effect of quercetin on inhibiting gefitinib‑activated non‑small cell lung cancer‑induced cell pyroptosis in cardiomyocytes via modulating mitochondrial autophagy mediated by the SHP2/ROS/AMPK/XBP‑1/DJ‑1 signaling pathway". Oncology Reports 53, no. 5 (2025): 57. https://doi.org/10.3892/or.2025.8890
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