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Cited by 313

The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

Open access
Ren, Xueying, Li, Yanchun, Zhou, Yi, Hu, Wanye, Yang, Chen, Jing, Qiangan, Zhou, Chaoting, Wang, Xu, Hu, Jiayu, Wang, Luyang, Yang, Jing, Wang, Hairui, Xu, Haifeng, Li, Huanjuan, Tong, Xiangmin, Wang, Ying, Du, Jing·2021·Redox Biology
DOI 10.1016/j.redox.2021.102122
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Abstract

Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.

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Metadata

Authors
Ren, X., Li, Y., Zhou, Y., Hu, W., Yang, C., Jing, Q., Zhou, C., Wang, X., Hu, J., Wang, L., Yang, J., Wang, H., Xu, H., Li, H., Tong, X., Wang, Y., & Du, J.
Venue
Redox Biology
Publisher
Elsevier BV
Published
2021-10
Volume
46
Pages
102122
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2021.102122
OpenAlex
W3197504514
Cited by
313
References
44
FWCI
31.21
Type
journal article
Language
en
Open access
gold

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CoChat. (2026). Citation check: Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis. https://app.cochat.ai/papers/10.1016/j.redox.2021.102122
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Ren, X., Li, Y., Zhou, Y., Hu, W., Yang, C., Jing, Q., Zhou, C., Wang, X., Hu, J., Wang, L., Yang, J., Wang, H., Xu, H., Li, H., Tong, X., Wang, Y., & Du, J. (2021). Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis. Redox Biology. https://doi.org/10.1016/j.redox.2021.102122

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