UA SRC Reports Novel Findings on NRF2 Controlling Iron Homeostasis and Ferroptosis

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The University of Arizona Superfund Research Center (UA SRC) Project 1 team recently reported novel findings regarding how the key antioxidant transcription factor NRF2 controls iron homeostasis – a self-regulating process to maintain stability – and can drive cancer cell death through ferroptosis, a form of cell death triggered by excessive lipid peroxidation.

NRF2, a transcription factor previously identified as a master regulator of many cellular processes, is an important modulator of arsenic’s adverse effects in various organs. It is believed to play an important role in the induction of diabetes by arsenic exposure. The recent findings show the translational value of inhibiting NRF2 to enhance the intracellular labile iron pool and drive cancer cell death through ferroptosis.

In this study, the investigators showed that NRF2 maintains iron homeostasis by controlling HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2; an E3 ubiquitin ligase for nuclear receptor coactivator 4 (NCOA4) and F-box and leucine rich repeat protein 5) and vesicle-associated membrane protein 8 (VAMP8; mediates autophagosome-lysosome fusion).

NRF2 knockout cells have low HERC2 expression, leading to a simultaneous increase in ferritin and NCOA4 and recruitment of apoferritin into the autophagosome. NRF2 knockout cells also have low VAMP8 expression, which leads to ferritinophagy blockage. Concordantly, deletion of NRF2 resulted in apoferritin accumulation in the autophagosome, an elevated labile iron pool, and enhanced sensitivity to ferroptosis.

These findings raise interesting questions about possible involvement of disruptions to iron homeostasis and ferroptosis in the effects of arsenic exposure on the development of metabolic diseases.

Publication:

Anandhan A, Dodson M, Shakya A, Chen J, Liu P, Wei Y, Tan H, Wang Q, Jiang Z, Yang K, Garcia JG, Chambers SK, Chapman E, Ooi A, Yang-Hartwich Y, Stockwell BR, Zhang DD. (2023) NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci Adv. Feb 3;9(5):eade9585. doi: 10.1126/sciadv.ade9585. Epub 2023 Feb 1. PMID: 36724221; PMCID: PMC9891695.