Fig. 2

Pseudohypoxia-related pheochromocytoma/paraganglioma (PPGL) and action mechanisms of hypoxia-inducible factor 2-alpha (HIF-2α) inhibitors. The HIF pathway is activated through the following processes: i) loss-of-function mutations in genes encoding molecules in the Krebs cycle (e.g., SDHx or FH), leading to succinate accumulation; ii) loss-of-function mutations in PHD1/2 or VHL, suppressing HIF-2α degradation. After succinate accumulation, HIF-2α/HIF-1β heterodimer formation following HIF-2α stabilization occurs in the nucleus, which activates the transcription of HIF target genes related to oncogenesis (e.g., angiogenesis- or cell cycle-related genes). HIF-2α inhibitors decrease the dimerization of HIF-2α with HIF-1β and suppress HIF target gene activation