Cysteine is one of the 20 amino acids that cells use to build proteins. While it plays important roles in the body, including the formation of iron-sulfur clusters and the production of glutathione—a key antioxidant—it can become harmful when present in high concentrations. A new study published in Nature Metabolism reveals that cysteine can extract iron from ferritin, a protein complex that normally stores iron safely. This iron is then transported to mitochondria, the energy-producing parts of the cell, where it disrupts iron-sulfur proteins and leads to cell death. This explains why cells typically convert cysteine into glutathione rather than letting it build up freely. Cysteine is essential for many cellular functions, but unlike other amino acids, it has a unique ability to release iron from ferritin. Once free, this iron can enter mitochondria and interfere with proteins that are crucial for energy production. This disruption causes mitochondrial failure and ultimately leads to cell death. The study highlights how this toxicity is specifically tied to the release and movement of iron, which is not observed with glutathione, a compound that shares a similar chemical structure with cysteine but does not release iron from ferritin. To investigate the mechanisms behind this toxicity, researchers used a genome-wide CRISPR screen, a technique that allows scientists to systematically disable genes to see which ones are involved in a particular process. They identified SLC25A28, a gene that transports iron into mitochondria, and proteins involved in breaking down ferritin. Experiments confirmed that cysteine can react with iron stored in ferritin, releasing it in a form that can enter mitochondria. This process does not occur with glutathione, suggesting that its chemical structure prevents it from releasing iron. Blocking the release of iron from ferritin or its transport into mitochondria prevented the toxic effects of high cysteine levels, confirming the role of iron movement in cysteine toxicity. The study also suggests that some cancers may have developed ways to manage high cysteine levels and avoid mitochondrial iron accumulation, which could be exploited for new cancer treatments. These findings help explain why cells prefer glutathione over free cysteine and offer new insights into how cells handle potentially harmful molecules without disrupting essential functions. Researchers are now exploring how cells detect and respond to these reactive molecules and how this process might be involved in diseases like cancer.