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Oestradiol-mediated ferroptosis defense shapes sex differences in acute kidney injury

Cell Death & Differentiation (2025)Cite this article

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Acute kidney injury (AKI) is a leading cause of morbidity and mortality. For decades, clinical observations and epidemiological studies have indicated that premenopausal women are less prone to AKI than men and postmenopausal women [1, 2]. However, the biological basis for this sex bias has remained largely unknown. In a recent Nature paper [3], Tonnus et al. provide a compelling mechanistic explanation, demonstrating that female renal tubules are inherently resistant to ferroptosis—a predominant mode of cell death involved in ischemic AKI—through oestradiol-mediated protection against this cell death.

AKI often arises from acute tubular necrosis, a pathological condition characterized by spatially propagating cell death along the nephron; this propagation has been shown to be driven, at least in part, by ferroptosis, a form of lipid peroxidation–driven cell death exacerbated by iron overload and impaired antioxidant defenses [4, 5]. Notably, previous studies reported that female mice were substantially more resistant to AKI and renal tubular ferroptosis propagation than male counterparts [6]. Using ischemia–reperfusion injury (IRI) models and ex vivo assays with isolated renal tubules, Tonnus et al. confirmed these findings and showed that ferroptotic cell death waves were prominent in male tubules but virtually absent in females; furthermore, while ferroptosis inhibitors have shown a robust protective effect in male mice, their benefit in females has been modest [3]. This resistance could not be explained by differences in the expression of classical ferroptosis regulators such as glutathione peroxidase 4 (GPX4).

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Fig. 1: Oestradiol-driven ferroptosis defenses underlie sex differences in acute kidney injury (AKI).

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Funding

The author has been supported in part by the Collaborative Accelerator for Transformative Research Endeavors grant, jointly awarded by The University of Texas at Austin and The University of Texas MD Anderson Cancer Center; and the N.G. and Helen T. Hawkins Distinguished Professorship for Cancer Research of MD Anderson Cancer Center.

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  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shengrong Wu, Li Zhuang & Boyi Gan

  2. The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Boyi Gan

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  1. Shengrong Wu
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  2. Li Zhuang
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SW prepared the figure. BG wrote the manuscript. LZ helped write and edit the manuscript.

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Correspondence to Boyi Gan.

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BG is an Editorial Board Member of Cell Death & Disease. Other authors declare no other competing interests.

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Wu, S., Zhuang, L. & Gan, B. Oestradiol-mediated ferroptosis defense shapes sex differences in acute kidney injury. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01573-w

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