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The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy

Acta Pharmacologica Sinica volume 45, pages 2229–2240 (2024)Cite this article

Abstract

Ferroptosis is an iron-dependent programmed cell death process that involves lipid oxidation via the Fenton reaction to produce lipid peroxides, causing disruption of the lipid bilayer, which is essential for cellular survival. Ferroptosis has been implicated in the occurrence and treatment response of various types of cancer, and targeting ferroptosis has emerged as a promising strategy for cancer therapy. However, cancer cells can escape cellular ferroptosis by activating or remodeling various signaling pathways, including oxidative stress pathways, thereby limiting the efficacy of ferroptosis-activating targeted therapy. The key anti-oxidative transcription factor, nuclear factor E2 related factor 2 (Nrf2 or NFE2L2), plays a dominant role in defense machinery by reprogramming the iron, intermediate, and glutathione peroxidase 4 (GPX4)-related network and the antioxidant system to attenuate ferroptosis. In this review, we summarize the recent advances in the regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy and explore the prospect of combining Nrf2 inhibitors and ferroptosis inducers as a promising cancer treatment strategy.

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Fig. 1: Scheme of ferroptosis activation pathways and the function of Nrf2 signaling in neutralizing ferroptosis.
Fig. 2: The regulation of Nrf2 signaling pathways during ferroptosis.
Fig. 3: Targeting Nrf2 signaling to synergy with ferroptosis-activating cancer therapies.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82273092) to LFF and Natural Science Foundation in Zhejiang province (LD22H160003) to XW.

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  1. These authors contributed equally: Xin Jiang, Min Yu

Authors and Affiliations

  1. Department of Medical Oncology, Zhejiang Key Laboratory of Multi-omics Precision Diagnosis and Treatment of Liver Diseases, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China

    Xin Jiang, Wei-kai Wang, Li-yuan Zhu, Xian Wang, Hong-chuan Jin & Li-feng Feng

  2. Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, School of Medicine, Zhejiang University, Jinhua, 321000, China

    Min Yu

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Contributions

XJ and MY wrote the manuscript; WKW researched the resources; LYZ polished the manuscript language; XW, HCJ and LFF edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hong-chuan Jin or Li-feng Feng.

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Jiang, X., Yu, M., Wang, Wk. et al. The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy. Acta Pharmacol Sin 45, 2229–2240 (2024). https://doi.org/10.1038/s41401-024-01336-2

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