Review expands the role of selenium metabolism in ferroptosis

For decades, selenium has been recognized as an essential micronutrient, and glutathione peroxidase 4 (GPX4)-a selenium-containing enzyme-has been widely regarded as the central guardian against ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation. But is GPX4 the whole story?

A new Mini-Review published in Ferroptosis and Oxidative Stress (FOS) argues that the answer is no.

In “Selenium metabolism, lipid peroxidation, and ferroptosis sensitivity: Lessons from selenium deficiency,” Professor Yoshiro Saito from Tohoku University, Japan propose that ferroptosis sensitivity is governed by a much broader selenium metabolic network. By examining the biological consequences of selenium deficiency, the authors provide a fresh framework for understanding how selenium metabolism regulates lipid peroxidation, antioxidant defense, and cellular susceptibility to ferroptosis.

Selenium deficiency as a window into ferroptosis biology

Selenium is indispensable for the synthesis of more than twenty-five human selenoproteins, many of which are essential for maintaining cellular redox homeostasis. Among them, GPX4 has attracted enormous attention because of its unique ability to detoxify phospholipid hydroperoxides and suppress ferroptosis.

However, the Review highlights that selenium deficiency affects far more than GPX4 alone. Limited selenium availability reshapes the entire selenoprotein network through hierarchical regulation of selenoprotein synthesis, altered selenium transport, and metabolic adaptation. These systemic changes ultimately determine how cells respond to oxidative stress and lipid peroxidation.

Rather than treating selenium deficiency simply as a nutritional disorder, the authors present it as a powerful experimental model for uncovering the molecular mechanisms that regulate ferroptosis sensitivity.

Beyond GPX4: expanding the ferroptosis landscape

Recent years have witnessed an explosion of discoveries connecting selenium metabolism with ferroptosis. The Review summarizes emerging evidence demonstrating that ferroptosis sensitivity is influenced by multiple layers of selenium biology, including selenium uptake, intracellular metabolism, selenocysteine biosynthesis, selenoprotein hierarchy, and antioxidant defense systems.

By integrating these findings, the authors move the field beyond the traditional GPX4-centered view and propose a more comprehensive model in which selenium metabolism functions as a dynamic regulatory network controlling lipid peroxidation and ferroptotic cell death.

This perspective also helps explain why selenium deficiency produces diverse biological consequences across different tissues and disease settings.

Implications for cancer and beyond

Because ferroptosis contributes to numerous pathological conditions-including cancer, neurodegenerative disorders, ischemia-reperfusion injury, metabolic diseases, and inflammatory diseases-understanding how selenium metabolism regulates ferroptosis may have broad translational implications.

The Review discusses how manipulating selenium metabolism could provide new opportunities to fine-tune ferroptosis sensitivity, either enhancing ferroptosis in cancer cells to improve anti-tumor therapies or protecting normal tissues from excessive lipid peroxidation in degenerative diseases.

As research into ferroptosis continues to evolve rapidly, selenium metabolism is emerging as more than a nutritional pathway-it is becoming a central determinant of cellular vulnerability to oxidative damage and regulated cell death.

By integrating advances in selenium biology, redox metabolism, and ferroptosis research, this Review provides researchers with a timely roadmap for understanding one of the fastest-growing areas in the field and highlights promising directions for future mechanistic and translational studies.