Hypoxia-inducible factor 1 (HIF-1) is the major transcription factor activated during hypoxia. it is composed of HIF-1alpha and HIF-1beta subunits. While HIF-1beta is constitutively expressed, HIF-1alpha is targeted to proteasome degradation under normoxic conditions. Under hypoxia, HIF-1alpha is stabilized and heterodimerizes with HIF-1beta. Iron chelators have also been reported to stabilize HIF-1alpha protein and activate HIF-1. In this study, we investigated the effects of dibenzoylmethane (DBM), a natural dietary compound and an iron chelator, on HIF-1 pathway. We found that DBM increases HIF-1alpha protein levels in a dose- and time-dependent manner. This induction was accompanied with activation of HIF-1, measured by reporter gene assay and increased production of its downstream target, the vascular endothelial growth factor. Mechanistically, HIF-1alpha was stabilized by DBM at a step prior to ubiquitination. The effect of DBM on HIF-1 and its low toxicity profile might be therapeutically beneficial in ischemic diseases. (C) 2003 Elsevier Science (USA). All rights reserved.