by Addison DeHaven, South Dakota State University

The Cyanalyzer is a patented technology from the Logue Lab that was used to confirm the production of cyanide in mammalian cells. The blue fluorescence in the right vessel is from a biological sample containing a high concentration of cyanide, whereas the left vessel is from a biological sample with a lower concentration of cyanide. Credit: South Dakota State University

Cyanide is a highly lethal chemical that has been used in warfare and poisonings for centuries—that was the general consensus on the naturally occurring chemical up until spring 2025. But in a global study published in Nature Metabolism, a research team from seven countries and 12 universities, including South Dakota State University, has upended the world’s consensus on cyanide. The researchers have found that while cyanide remains highly poisonous, it also plays a fundamental role in normal cell function.

Brian Logue, professor and head of SDSU’s Department of Chemistry, Biochemistry and Physics, is one of the country’s leading experts on cyanide. Logue and Moustafa Khalaf, an SDSU research scientist, played a critical role in the research process by confirming and quantifying cyanide production in human cells.

“The identification of endogenous cyanide production in mammals represents a significant advancement in cell biology and metabolism,” Logue said. “This research highlights the dual nature of cyanide, acting as both a toxin at high concentrations and a crucial signaling molecule at low concentrations.”

A naturally produced poison?

Previously, scientists had only known cyanide to be naturally produced in certain types of bacteria and plants. The process of producing cyanide in minute quantities had never been demonstrated in mammalian cells.

Through experiments on mice and human cells, the research team, led by scientists from Switzerland, observed that hydrogen cyanide was consistently present in the cells and organisms. This was supported by the detection of cyanide in the liver of mice and humans as well as in the bloodstream. The chemical, they found, was produced naturally, suggesting a role in fundamental physiological processes.

According to Khalaf, cyanide’s natural production in the body is linked to glycine, an amino acid, which stimulates its production in the liver cells. The research team was able to determine this interaction by adding glycine to cell cultures. By adding glycine, the production of hydrogen cyanide increased.

Still, cyanide is highly lethal and is toxic at certain doses. How does the human body regulate internal cyanide levels to prevent toxicity?

Confocal microscopy analysis of cyanide and HOCl generation in HepG2 cells. Credit: Nature Metabolism (2025). DOI: 10.1038/s42255-025-01225-w

An enzyme, rhodanese, plays a critical role in toxicity prevention. It converts hydrogen cyanide into thiocyanates, nontoxic salts, which are eliminated from the body, Khalaf explained.

“Echoing the principle of Paracelsus, the research indicates that the dose determines whether cyanide acts as a poison or has beneficial effects,” Khalaf said.

Logue and Khalaf confirmed and quantified the cyanide production in the cells by using their novel technique and patented technology, the Cyanalyzer.

Potential therapeutic benefits and applications

This discovery has far-reaching potential therapeutic benefits and applications, many of which are in the medical field. Experiments conducted during this study showed low concentrations of hydrogen cyanide enhance cell survival during oxygen deprivation. This suggests cyanide plays a role in the body’s protective mechanisms against conditions like stroke, Khalaf noted.

“The discovery of cyanide’s protective effects during hypoxia presents potential therapeutic strategies for stroke by enhancing brain cell resilience to oxygen shortage,” Khalaf said.

Other findings show that certain diseases—nonketotic hyperglycinemia being one—cause the body to produce excessive amounts of hydrogen cyanide. The rare disease causes glycine to build up in tissues and organs. It is most damaging to babies as excessive glycine can build up in the brain, leading to neurological disorders. Previously, there was almost no treatment for this disease, but this research, with fresh insight into glycine and rhodanese, may lead to new therapies.

The lead author in the study, Csaba Szabo, believes these findings will “fundamentally change the way we think about cell biology and metabolism.”

Future research will focus on further understanding the precise roles of endogenous cyanide in health and disease, exploring its therapeutic potential while carefully managing its toxicity.

More information: Karim Zuhra et al, Regulation of mammalian cellular metabolism by endogenous cyanide production, Nature Metabolism (2025). DOI: 10.1038/s42255-025-01225-w

Journal information:Nature Metabolism

Provided by South Dakota State University

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