A compound that blocks iron-containing enzymes in the brain improves recovery following brain hemorrhage, a new study in rodents shows, and it works in an unexpected way. Instead of binding all free iron released from burst blood vessels, it targets a small family of iron-containing enzymes without affecting total iron - an element required for various physiological processes such as mitochondrial function, cell signaling, and cell division. Brain hemorrhage, bleeding inside the brain caused by a ruptured blood vessel that can lead to death or disability, is growing in prevalence. Common causes include stroke, blunt trauma, brain tumors, and use of blood-thinners. Blood cells that have leaked from burst vessels can break down, releasing toxic products like iron that damage surrounding tissues. Compounds that bind to iron and remove it from the body, known as iron chelators, have been shown to protect the brain during bleeding. However, these compounds can have wide-ranging side effects since they can also bind to iron in other parts of the brain where healthy cells need it to survive. A challenge in developing iron chelators for use in human therapy is to reduce iron accumulation without disrupting iron-dependent cellular functions. Here, Saravanan Karuppagounder and colleagues identified a more selective iron chelator compound that they named adaptaquin. In a series of cell-based studies, they showed that it both blocked a family of iron-containing, oxygen-sensing enzymes called hypoxia-inducible factor prolyl-hydroxylases (HIF-PHD) and, critically, protected neurons by activating genes that protect them from oxidative stress. The researchers used a series of molecular and pharmacological tools to show that, both in vitro and in vivo, inhibiting HIF-PHD with adaptaquin may be neuroprotective after a brain hemorrhage event. Closer inspection revealed that the drug had little effect on either iron in the brain or, unexpectedly, the target of the oxygen-sensing enzymes. Instead, adaptaquin seemed to work by blocking a protein called ATF4 that drove cell death in neurons. Altogether, the findings support further development of adaptaquin as a potential treatment for brain bleeding.