Estrogen's Role in Preventing Ferroptosis Offers Insights into Kidney Disease Risks Across Genders

Acute kidney injury remains a common and challenging condition due to the absence of targeted therapies.

For many years, medical professionals have noted that women are less likely than men to experience acute kidney failure. This observation, first reported in 1940 and confirmed by various studies, continues to puzzle researchers.

A new study published in Nature from scientists at Medical Faculty Mannheim, Heidelberg University, offers a novel explanation for this phenomenon by investigating estrogen's role in regulating ferroptosis—a form of iron-dependent cell death.

The research highlights how estrogen inhibits ferroptosis, which could elucidate why women become more susceptible to kidney disease after menopause when hormone production drops. Specifically, the study focuses on estrogen and its hydroxylated metabolites like 2-hydroxyestradiol, demonstrating their protective effects via both genomic and non-genomic mechanisms.

Notably, estrogen functions like a natural drug that reduces ferroptosis by initiating various biological defense systems, including controlling hydropersulfides—substances acting as antioxidants to curb ferroptosis—and regulating ether lipids crucial for cell membrane integrity. The study reveals the protective role of estrogen and its receptor interactions in different physiological processes.

These insights clarify gender differences in kidney disease susceptibility and open avenues for new treatments. Moreover, these findings could extend beyond renal medicine, impacting fields such as cancer research where ferroptosis plays a significant role.

"Our work suggests that the implications of estrogen’s protective effects may reach far beyond the kidneys, influencing conditions like heart attacks and stroke, where women typically have an advantage over men. Additionally, it might contribute to explaining women's longer life expectancy," says Professor Andreas Linkermann, Director at the University Medical Center Mannheim and senior author.

The study’s implications on broader health contexts and potential ethical concerns, such as organ transplantation, underscore a new research direction into ferroptosis's impact.

Tom Vanden Berghe, an expert in the field, acknowledges the paper’s significance. In his accompanying article "Estrogen defends against kidney damage caused by iron-dependent cell death" published in the same issue of Nature, he states: "This work marks a significant step in understanding sex differences related to acute kidney failure and adds physiological importance to ferroptosis beyond cancer and neurodegeneration."

Vanden Berghe notes, "These findings might explain why postmenopausal women are more vulnerable to acute kidney injury. They also pave the way for exploring estrogenic metabolites or inhibitors of ferroptosis as potential therapeutic strategies. As Ferroptosis is increasingly recognized as a central mechanism in tissue injury, this research emphasizes the importance of considering sex as a biological variable."