Cystathionine β‐synthase is required for body iron homeostasis

Cystathionine β-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide (H2S). In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 (IL-6) pathway utilized in the regulatory systems of H2S and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knock-out (CBS-/-) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron-overload is the reduced iron utilization due to suppressed erythropoiesis, which is consistent with an increase in IL-6 and the reduced expression of erythropoietin. Importantly, in the liver, an absence of CBS caused both a reduction in the transcriptional factor NRF2 and an upregulation of hepcidin that lead to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS-overexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. Our findings thus point to a previously unknown, yet critical role of CBS in iron homeostasis of the body, and the liver in particular. It is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway, but also in those related to CBS. This article is protected by copyright. All rights reserved.