Hephaestin

Hephaestin is a copper-containing, membrane-bound ferroxidase that catalyzes the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+). In humans, the enzyme is encoded by the HEPH gene and is predominantly expressed by intestinal enterocytes, where it plays a key role in dietary iron absorption. The protein is localized to the basolateral surface of enterocytes and functions in concert with the iron exporter ferroportin (SLC40A1).

By converting Fe2+ to Fe3+, hephaestin facilitates the loading of iron onto transferrin in the bloodstream, enabling iron transport to tissues throughout the body. This oxidation step is important because transferrin preferentially binds ferric iron, and proper iron export from enterocytes depends on this ferric form.

Regulation of iron homeostasis involves hepcidin and ferroportin; hepcidin downregulates ferroportin to limit iron export during inflammation or iron overload. Hephaestin supports efficient iron efflux by ensuring the iron is in the appropriate oxidation state for transferrin binding.

Clinical and research relevance: loss or dysfunction of hephaestin impairs iron export from enterocytes, leading to iron accumulation in the intestinal mucosa and reduced serum iron, with features of iron-restricted erythropoiesis and microcytic anemia in model systems. In mice lacking hephaestin, hypoferremia and iron maldistribution have been observed. Hephaestin is related to ceruloplasmin, another multicopper oxidase, and has homologs such as hephaestin-like protein (HEPHL1) in vertebrates.

See also: iron metabolism, ferroportin, transferrin, ceruloplasmin.