Selenium is a micronutrient of enormous importance for human health. Its biological functions are associated with selenoproteins, which have selenocysteine ​​in their structure. Selenoproteins are generally involved in cellular redox functions, such as those performed by the vital antioxidant enzyme glutathione peroxidase 4 (GPX4). This enzyme protects membrane lipids and inhibits cell death by ferroptosis. Therefore, selenocysteine metabolism is essential for maintaining cellular function and allowing life.

In a recent publication in Molecular Cell, an international team of researchers announced the discovery of a new pathway for selenocysteine metabolism mediated by the antioxidant enzyme peroxiredoxin 6 (PRDX6). They also found that elevated levels of PRDX6 are associated with a highly aggressive subtype of neuroblastoma, suggesting this mechanism could potentially be targeted to induce ferroptosis in tumor cells.

According to the authors, this study advances the understanding of selenocysteine metabolism and selenoprotein biosynthesis by revealing a novel function for PRDX6. “Until recently, it was believed that there was only one pathway for selenocysteine metabolism. However, for a cell, having parallel pathways is important because, if a mutation occurs in selenocysteine lyase, for example, selenoprotein production will halt, making the cell more susceptible to ferroptosis,” explained Alex Inague, co-first author of the study.

The research was led by José Pedro Friedmann Angeli from the University of Würzburg, Germany, Sayuri Miyamoto from the Instituto de Química at the University of São Paulo (USP) and a member of RIDC Redoxoma, and Hamed Alborzinia from the Heidelberg Institute for Stem Cell Technology and Experimental Medicine and the German Cancer Research Center. Inague conducted the research during his Ph.D. at IQ-USP, under Miyamoto’s supervision, and completed an internship in Angeli’s lab. The study also involved Redoxoma researchers Flavia Meotti and Luis E.S. Netto from USP, along with collaborators from Germany, the United States, and Spain.

Ferroptosis and Selenoproteins

Ferroptosis is characterized by the accumulation of lipid peroxidation products catalyzed by iron ions, resulting in membrane rupture and cell death. “Our cells need fluid membranes so that there is a regulated transport mechanism via proteins between the intra- and extracellular environments. Yet, we exist in an oxygen-rich environment that generates free radicals and oxidants. The polyunsaturated fatty acids in the membranes are oxidized, generating phospholipid hydroperoxides that, in the presence of metals, break down, forming more lipid radicals, which propagate chain reactions, destabilizing the membrane,” explained Miyamoto.

According to the researchers, the mechanisms of ferroptosis regulation have attracted increasing interest due to the association of this type of cell death with several pathological conditions, including cancer, neurodegeneration, and tissue damage. Inducing ferroptosis may be a promising approach to treating certain types of cancer, such as neuroblastoma, B-cell lymphoma, and undifferentiated melanoma.

In cells, the primary defense against ferroptosis is a selenoprotein, GPX4, which protects membranes from oxidation.

Selenoproteins are rare; only 25 exist in the human proteome. Selenocysteine is similar to cysteine but the sulfur atom is replaced by selenium. This substitution, however, is not simple, requiring multiple steps for synthesis.

“Selenocysteine is encoded by the stop-codon UGA, which usually signals the end of protein synthesis. If selenium is absent, translation halts without producing selenoproteins. Cells regulate this stop-codon recoding and selenoprotein expression through a complex system involving numerous factors,” said Inague.

This is because selenide is very reactive. “A fully efficient transport mechanism is needed to take the selenium consumed in the diet to the proteins synthesized from it,” Miyamoto says.

In his research, Inague identified a correlation between PRDX6, enzymes involved in selenium metabolism, and expression levels of selenoproteins such as GPX4. PRDX6 also reduces phospholipid hydroperoxides, but kinetic studies have shown that it does so at a much slower rate than GPX4.

Using screening techniques with CRISPR/Cas9 gene-editing technology on neuroblastoma cell lines, the researchers found that PRDX6 acts independently of an enzyme called selenocysteine lyase (SCLY), considered essential in selenocysteine metabolism.

Through a series of experiments using recombinant PRDX6, they demonstrated that PRDX6 can bind to different selenium compounds, suggesting it may play a role in selenium transport and constitute an alternative pathway for selenocysteine metabolism.

PRDX6 is highly conserved evolutionarily and is present in various organisms, from archaea and bacteria to humans. It is found in practically all our organs, mainly the lungs, brain, liver, kidneys, and testicles.

Cancer and Neurodegenerative Diseases

Neuroblastoma is a tumor that develops from cells of the nervous system and mainly affects children under 10 years old. Its most aggressive form relies on a selenoprotein P receptor (LRP8) for ferroptosis suppression and proliferation. Given this dependency, researchers investigated the effect of PRDX6 on neuroblastoma.

For this, they used a xenograft model, implanting patient-derived cancer cells into animals to induce tumor growth. Modified cells were then implanted into the animals’ adrenal glands. Animals with deletions of both PRDX6 and SCLY had smaller tumors and survived longer compared to those with intact enzymes. This suggests that without PRDX6 and SCLY, the selenium pathway is compromised, leading to reduced GPX4 expression in tumor cells, which become more susceptible to ferroptosis.

However, it is premature to propose PRDX6 inhibition as a therapeutic approach. According to the authors, further studies are needed to determine whether PRDX6 could serve as a drug target.

In contrast, preventing ferroptosis may also hold therapeutic potential. “Evidence suggests ferroptosis may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). So, it is a pathway that, if we understand how it happens, we can prevent this death by ferroptosis. There are two sides: we can induce ferroptosis for therapeutic purposes in cancer or prevent ferroptosis and treat a neurodegenerative disease. So, we try to explore both directions,” Miyamoto said.

The article PRDX6 contributes to selenocysteine ​​metabolism and ferroptosis resistance can be accessed here