Arsenic contamination poses a significant threat to global public health, particularly due to its high toxicity and widespread occurrence in the environment. Research recently published in the ‘Journal of Hazardous Materials’ has shed light on a molecular regulatory module that underlies the process of ferroptosis, a form of cell death, as induced by sodium arsenite—a common compound of arsenic. This groundbreaking study offers novel insight into the mechanism of arsenic-induced kidney injury, a concern for human health due to potential exposure via contaminated drinking water and foodstuffs.

DOI: 10.1016/j.jhazmat.2023.133038

Understanding Ferroptosis: The Role of the G3BP1-FBXL5-IRP2 Axis

Ferroptosis is a recently discovered type of programmed cell death that is specific to iron-dependent cells. It is characterized by the accumulation of lipid peroxides, which are toxic to the cell. Researchers Liu Qian, Wang Fengli, Chen Yingxian, Cui Hengkang, and Wu Hao conducted a study revealing that sodium arsenite does not just induce ferroptosis in mammalian HEK293, MEF, and HT1080 cells but also causes acute kidney injury in mice associated with this form of cell death. Their findings were published in a paper titled “A regulatory module comprising G3BP1-FBXL5-IRP2 axis determines sodium arsenite-induced ferroptosis.”

The Axis at Work

The study identifies a regulatory module where G3BP1 (an RNA-binding protein and a component of stress granules) plays a critical role. G3BP1 is revealed as essential for the onset of ferroptosis resulting from exposure to sodium arsenite. It acts independently of stress granules to stabilize iron regulatory protein 2 (IRP2), a unique controller of cellular iron levels. G3BP1 achieves this through interactions with FBXL5 mRNA, the genetic code for an E3 ligase component crucial for the ubiquitination and subsequent degradation of IRP2. When there’s sodium arsenite intoxication, the G3BP1-FBXL5-IRP2 axis is accelerated, leading to heightened levels of cellular labile free iron. This increase is directly responsible for the lipid peroxidation and cell death detected in the exposure scenarios.

Implications and Potential Applications

The findings from this study are significant for public health and clinical settings. Given the widespread issue of arsenic in drinking water in various regions globally, understanding the molecular mechanisms underpinning arsenic-induced kidney damage is vital for developing therapeutic interventions. By targeting the G3BP1-FBXL5-IRP2 regulatory module, it may be possible to devise strategies to prevent or treat arsenic-induced ferroptosis in kidney cells.


1. Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., … & Stockwell, B. R. (2012). Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell, 149(5), 1060–1072.

2. Hassannia, B., Vandenabeele, P., & Vanden Berghe, T. (2019). Targeting Ferroptosis to Iron Out Cancer. Cancer Cell, 35(6), 830–849.

3. Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., … & Jiang, X. (2017). Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171(2), 273–285.

4. Torti, S. V., & Torti, F. M. (2013). Iron and cancer: More ore to be mined. Nature Reviews Cancer, 13(5), 342–355.

5. Angeli, J. P. F., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., … & Conrad, M. (2014). Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology, 16(12), 1180–1191.

Declaration of Competing Interest: The authors declared financial support from Huazhong Agricultural University, while also stating no competing financial interests or personal relationships that could influence the work reported in this paper.

1. Sodium arsenite toxicity
2. Ferroptosis mechanism
3. Arsenic-induced kidney injury
4. Iron-dependent cell death
5. G3BP1-FBXL5-IRP2 regulation

In summary, the newly identified G3BP1-FBXL5-IRP2 regulatory module provides essential insights into the sodium arsenite-triggered process of ferroptosis and its relation to acute kidney injury, a discovery that holds promise for the development of targeted treatments to combat the detrimental health effects of arsenic exposure.