Acute kidney injury occurs frequently and still represents a major clinical challenge due to the lack of a targeted therapy. For decades, clinicians have observed that women are less susceptible to acute kidney failure than men. This is not a new finding; in fact, this was reported as early as 1940 and was confirmed in epidemiological studies. However, to this day, the underlying cause of this effect remains a mystery.
In a paper published in Nature, scientists at the Medical Faculty Mannheim, Heidelberg University have now provided a key, novel explanation for this phenomenon.
In the study, they focused on the female sex hormone estrogen and the process of ferroptosis, an iron-dependent form of regulated cell death. They discovered that estrogen blocks ferroptosis, explaining how the protective effect on the kidneys is lost with menopause when sex hormone production declines. Interestingly, estrogen and specifically its hydroxylated derivatives—such as 2-hydroxyestradiol—are key mediators of a complex protective mechanism through genomic and non-genomic mechanisms.
Remarkably, estrogen acts like an intrinsic protective drug against ferroptosis by itself. Additionally, by binding to its receptor, estrogen initiates various biological systems that can be considered defense mechanisms against ferroptosis, including the regulation of hydropersulfides, which act as radical scavengers to keep ferroptosis in check. Estrogen receptor engagement additionally counteracts the alteration of ether lipids—important components of the cell membrane—thereby also inhibiting ferroptosis.
Credit: by Eva Maria Wellnitz, Universitätsmedizin Mannheim