Estrogen's Role in Preventing Ferroptosis Offers New Insights Into Sex Differences in Kidney Disease Risk

Recent research has shed light on the protective effects of estrogen against acute kidney injury (AKI) by inhibiting ferroptosis, a form of iron-dependent programmed cell death. For decades, clinical observations have noted that women tend to be less susceptible to kidney failure compared to men, a difference first documented as early as the 1940s. However, the biological mechanisms behind this disparity have remained elusive.

A groundbreaking study published in Nature by scientists at Heidelberg University’s Medical Faculty in Mannheim uncovers a key piece of this puzzle. The researchers focused on estrogen, the primary female sex hormone, and its ability to block ferroptosis. They found that estrogen interferes with the process of ferroptosis through various mechanisms, including genomic and non-genomic pathways mediated by hydroxylated derivatives like 2-hydroxyestradiol.

Estrogen acts as an intrinsic protector against ferroptosis by directly inhibiting its initiation. It does so by regulating radical scavengers called hydropersulfides, which neutralize harmful radicals, and by preventing changes in ether lipids—crucial components of cell membranes—thereby safeguarding kidney cells from damage. The decline in estrogen production after menopause explains why women become more vulnerable to AKI and other related kidney diseases.

The findings not only clarify sex-based differences in kidney disease risk but also open doors to novel therapies. Modulating ferroptosis through estrogenic pathways could potentially help in developing targeted treatments for kidney injuries and other conditions where ferroptosis is involved. Interestingly, the implications extend beyond the kidneys, touching on gender differences observed in diseases like heart attacks and strokes, where women often show greater resilience.

Furthermore, the research raises intriguing ethical considerations for transplant medicine, such as whether organs from premenopausal female donors might be more resistant to injury due to ferroptosis, potentially influencing organ valuation.

Expert commentary by Tom Vanden Berghe emphasizes that this discovery expands the understanding of ferroptosis across various diseases. The study underscores the importance of considering biological sex in disease research and points to estrogen or ferroptosis inhibitors as promising therapeutic avenues.

In conclusion, the study advances our knowledge of how sex hormones contribute to disease resistance and highlights the potential for hormone-based therapies to combat tissue injuries caused by ferroptosis.