HEPH (hephaestin) is a multicopper ferroxidase essential for systemic iron homeostasis, functioning as a plasma membrane-bound enzyme that oxidizes ferrous iron (Fe2+) to ferric iron (Fe3+) 1. HEPH works in conjunction with ferroportin to facilitate iron export from cells, particularly in the small intestine where it is critical for dietary iron absorption 1. The enzyme contains six copper atoms that serve as electron acceptors during the four-electron reduction of dioxygen coupled to iron oxidation 1. HEPH plays partially overlapping roles with ceruloplasmin in brain iron homeostasis, facilitating iron export from glial cells to make iron available to neurons 2. Deficiency in both HEPH and ceruloplasmin leads to iron accumulation in glial cells, neuronal iron deficiency, and neurodegeneration with ataxia and tremor 2. In the kidney, HEPH protects against iron-induced toxicity, as knockout mice develop renal iron deposition, proteinuria, and compromised structural integrity 3. HEPH expression is regulated by zinc through a PI3K-CDX2 pathway in intestinal cells 4, and its dysregulation has been implicated in colon cancer chemotherapy resistance 5 and glioblastoma 6.