Model for the therapeutic action of MK-6482 in Vhl^R200W, Irp1-KO, and double-mutant Vhl^R200W;Irp1-KO mice. The expression of Hif-2α protein is regulated at multiple levels. Irp1, which is most likely the predominant IRE-binding protein in renal interstitial fibroblast and pulmonary endothelial cells, binds to the Hif-2α-IRE at the 5′ UTR and thus represses Hif-2α translation. Thus, Irp1 deficiency results in an increased Hif-2α expression through derepression of Hif-2α translation. In contrast, the Vhl protein promotes degradation of Hif-2α (as well as Hif-1α) under normoxic conditions. However, Vhl^R200W does not mediate normal Hif-2α degradation. Thus, either Irp1 deletion or the Vhl^R200W mutation leads to high levels of Hif-2α and augmented levels of Hif-2α target genes, including EPO, endothelin-1 (ET-1), and Cxcl-12. MK-6482, the second-generation, specific inhibitor of Hif-2α, binds to the internal cavity in the PAS-B domain of Hif-2α, distorting its structure and disrupting the formation of Hif-2α-Hif-1β dimers, thus inhibiting Hif-2α–dependent transcriptional activity and thereby reducing the elevated expression levels of Hif-2α targets in Vhl^R200W, Irp1-KO, and double-mutant Vhl^R200W;Irp1-KO mice.