A team of researchers at Helmholtz Munich, in collaboration with Tohoku University, has discovered a key protein that regulates ferroptosis, a form of programmed cell death driven by oxidative stress. Ferroptosis has become a focal point in scientific research due to its potential applications in treating therapy-resistant cancers and neurodegenerative diseases.

The focus of the study was on peroxiredoxin 6 (PRDX6), a protein that plays a vital role in regulating ferroptosis. PRDX6 also functions as a selenium carrier, an essential component for protecting cells from oxidative damage. This discovery positions PRDX6 as a potential target for therapies aimed at both cancer and neurodegenerative conditions.

Published in Molecular Cell on November 14, 2024, the study was led by Dr. Eikan Mishima, Senior Scientist at Helmholtz Munich and Tohoku University, alongside Professor Marcus Conrad, also from Helmholtz Munich’s Institute of Metabolism and Cell Death.

PRDX6: Selenium Carrier and Ferroptosis Regulator

Selenium is a trace element essential for human health, integral to several key selenoproteins. Among these, glutathione peroxidase 4 (GPX4) is particularly important, as it helps prevent ferroptosis by mitigating lipid peroxidation. The researchers’ focus on PRDX6 arose from its peroxidase activity, akin to GPX4. Although PRDX6 is less potent than GPX4 in its peroxidase function, the team discovered that cells lacking PRDX6 were more prone to ferroptosis, especially in cancer cells. This unexpected observation led to the revelation of PRDX6’s role in selenium metabolism.

PRDX6 not only has peroxidase activity but also acts as a selenium carrier protein. This function is crucial for transporting selenium within cells, allowing its incorporation into selenoproteins like GPX4, thus helping to regulate ferroptosis sensitivity.

As Dr. Mishima noted, “The molecular identity of PRDX6 as a selenium carrier had long been speculated, but our study confirmed it.”

Impact of PRDX6 Deficiency on Tumors and the Brain

In animal studies, the absence of PRDX6 led to reduced tumor growth, highlighting the protein’s significance in cancer biology. Additionally, PRDX6-deficient mice exhibited lower levels of selenoproteins in the brain, pointing to the protein’s crucial role in brain health and neuroprotection. This finding suggests that PRDX6 is a critical factor in both cancer progression and brain function.

Therapeutic Potential for Cancer and Neurodegenerative Diseases

These findings open up potential new avenues for treating both cancer and neurodegenerative diseases. Tumors that are resistant to conventional therapies may become more susceptible to ferroptosis if PRDX6 is inhibited, offering a novel strategy for combating aggressive cancers. In contrast, preserving PRDX6 function in the brain could offer a way to slow the progression of neurodegenerative diseases by maintaining selenoprotein levels and preventing neuronal ferroptosis.

Professor Conrad pointed out that the discovery of PRDX6’s role in selenium metabolism could revolutionize therapeutic approaches for both cancer and neurodegeneration. The team’s work is complemented by a related study from the Friedmann Angeli lab at Würzburg University, which was also published in the same issue of Molecular Cell. Together, these studies underline the importance of PRDX6 in health and disease.

Commentary by YourDailyFit columnist Alice Winters:

The identification of peroxiredoxin 6 (PRDX6) as a critical regulator of ferroptosis marks a significant advance in the scientific understanding of both cancer and neurodegenerative diseases. This research not only elucidates a new molecular mechanism but also paves the way for potential therapeutic interventions. By exploring PRDX6’s dual role as both a peroxidase and a selenium carrier, the study provides novel insights into how selenium metabolism can influence cellular stress responses, opening up possibilities for precision medicine.

The therapeutic implications of this discovery are particularly intriguing. Ferroptosis has gained attention in recent years due to its potential to target hard-to-treat cancers. The ability to sensitize cancer cells to ferroptosis via PRDX6 inhibition could represent a groundbreaking approach in oncology, especially for therapy-resistant or metastatic tumors. Additionally, neurodegenerative diseases, such as Alzheimer’s and multiple sclerosis, have long been elusive in terms of treatment development. PRDX6’s role in protecting neurons from oxidative stress could provide a new pathway for managing these conditions.

However, while the findings are compelling, further research is needed to explore the clinical applicability of these results. A key consideration will be the safe modulation of PRDX6 activity in humans, given the delicate balance between promoting ferroptosis in tumors and preventing neuronal damage in the brain. Additionally, the broader implications of selenium metabolism on human health necessitate careful attention to potential side effects or unintended consequences of altering this pathway.

In conclusion, this research represents an exciting breakthrough with profound implications for cancer therapy and neurodegenerative disease treatment. As we continue to understand the full scope of PRDX6’s functions, its potential as a therapeutic target could help usher in a new era of treatments based on the precise regulation of ferroptosis.