Hypoxia, iron, and ferroptosis: a novel perspective on pheochromocytoma progression and therapy

Abstract

Objectives: All pheochromocytomas (PCCs) have metastatic potential, and inoperable cases often resist multidisciplinary treatment. Pheochromocytomas are broadly divided into cluster 1 (hypoxia signaling) and cluster 2 (kinase pathway). Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is induced under hypoxia and may target therapy-resistant malignancies. However, its relevance in PCCs remains entirely unknown. We therefore examined the characteristics of PCCs prone to ferroptosis and evaluated their potential as a therapeutic target.

Design: We performed a retrospective and experimental study to characterize ferroptosis in PCCs and evaluate its clinical significance.

Methods: We assessed ferroptosis sensitivity and characterized the induction and execution mechanisms in primary cultured cells derived from resected PCCs. The clinical significance of ferroptosis was examined using both 53 PCC tumors and transcriptomic and genetic data from the Gene Expression Omnibus (GEO) database. To investigate the tumor-suppressive function of ferroptosis inducers, a xenograft model was established using PC12 cells treated with dimethyl sulfoxide (DMSO) or ferroptosis inducers.

Results: Ferroptosis susceptibility varied among PCCs. Ferroptosis-prone cells showed elevated intracellular Fe2+ levels and upregulation of genes involved in Fe2+ accumulation. Analysis of the 53 PCC tumors and GEO data revealed that cases with higher ferroptosis marker expression were more frequently observed in younger patients and were enriched in cluster 1 genotypes. Cluster 1 mutations and hypoxia were associated with transferrin receptor (TFRC) upregulation, enhancing extracellular iron uptake and facilitating ferroptosis. In contrast, cluster 2 tumors relied on ferritinophagy and heme degradation, suggesting reliance on intracellular iron pools. Importantly, ferroptosis inducers markedly reduced tumor volume in xenografts, underscoring their therapeutic potential.

Conclusions: Exploiting mutation-specific dysregulation of iron metabolism to trigger ferroptosis may provide a novel therapeutic strategy for therapy-resistant pheochromocytomas.

Keywords: ferroptosis; hypoxia; iron; pheochromocytoma.