Transcription factors in ferroptotic cell death

Abstract

Ferroptosis, a form of regulated cell death, is characterized by an excessive degree of iron accumulation and lipid peroxidation. Although it was originally identified only in cells expressing a mutant RAS oncogene, ferroptosis has also been found in normal cells following treatment by small molecules (e.g., erastin and RSL3) or drugs (e.g., sulfasalazine, sorafenib, and artesunate), which target antioxidant enzyme systems, especially the amino acid antiporter system xc and the glutathione peroxidase GPX4. Dysfunctional ferroptosis is implicated in various physiological and pathological processes (e.g., metabolism, differentiation, and immunity). Targeting the ferroptotic network appears to a new treatment option for diseases or pathological conditions (e.g., cancer, neurodegeneration, and ischemia reperfusion injury). While the molecular machinery of ferroptosis remains largely unknown, several transcription factors (e.g., TP53, NFE2L2/NRF2, ATF3, ATF4, YAP1, TAZ, TFAP2C, SP1, HIF1A, EPAS1/HIF2A, BACH1, TFEB, JUN, HIC1, and HNF4A) play multiple roles in shaping ferroptosis sensitivity through either transcription-dependent or transcription-independent mechanisms. In this review, we summarize recent progress in understanding the transcriptional regulation underlying ferroptotic cell death, and discuss how it has provided new insights into cancer therapy.

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Fig. 1: Key regulators of ferroptosis.
Fig. 2: Role of transcription factors in ferroptotic cell death.

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Acknowledgements

We apologize to those whose work was not referenced either due to space limitations or our oversight. We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. D.T. is supported by grants from the US National Institutes of Health (R01CA229275 and R01CA160417). R.K. is supported by a grant from the US National Institutes of Health (R01CA211070).

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Dai, C., Chen, X., Li, J. et al. Transcription factors in ferroptotic cell death. Cancer Gene Ther 27, 645–656 (2020). https://doi.org/10.1038/s41417-020-0170-2

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