Directly binds and inhibits HIF-2α (EPAS1), preventing its dimerization with HIF-1β (ARNT) and blocking transcription of HIF-2α target genes including VEGF, EPO, and metabolic enzymes. In the LITESPARK-015 Phase 2 trial (NCT04924075) in locally advanced or metastatic pheochromocytoma and paraganglioma, belzutifan achieved an 85% disease control rate and 26% overall response rate, becoming the first oral and second FDA-approved therapy for metastatic PPGL (Jimenez et al., J Clin Endocrinol Metab 2026, PMID 42573142). This validates HIF-2α inhibition as a clinical target directly downstream of SDHx mutation: SDH loss → succinate accumulation → PHD inhibition → constitutive HIF-2α stabilization — the same pseudohypoxic mechanism as VHL deficiency. Beyond radiographic response, belzutifan improved blood pressure control and quality of life in PPGL patients; the predominant adverse effect is mechanism-based grade 1–3 anemia (EPO suppression).