Structural Insights into Metal-Chelating Natural Inhibitors of Factor Inhibiting HIF-1α

Factor inhibiting HIF-1α (FIH) is a 2-oxoglutarate-dependent oxygenase that controls hypoxia signaling and metabolic homeostasis by hydroxylating HIF-1α. Although selective pharmacological inhibition of FIH represents an emerging therapeutic strategy for metabolic disorders, structurally diverse natural inhibitors remain largely unexplored. Here, we identified five natural FIH inhibitors spanning distinct phytochemical classes, including three flavonoids (wogonin, luteolin, morin), a coumarin (isofraxidin), and an anthraquinone (rhein). Co-crystal structures revealed that structurally diverse natural products converge on a common bidentate metal-chelation geometry within the FIH active site despite substantial differences in scaffold architecture. Among these inhibitors, wogonin most closely mimicked the orientation of the HIF-1α Asn803 side chain within the substrate-binding cleft, resulting in inhibitory potency comparable to that of the 2-oxoglutarate analog N-oxalylglycine. These findings establish the first structural framework for natural-product-based FIH inhibition and demonstrate that structurally distinct natural inhibitors adopt a conserved metal-chelation geometry within the FIH active site. This framework provides a basis for the future development of metabolically oriented FIH inhibitors.