The role of ferroptosis in the pathogenesis of pulmonary hypertension and its therapeutic potential.

Pulmonary hypertension (PH) is a pathophysiological state characterized by progressively elevated pulmonary vascular resistance and pulmonary arterial pressure. Its core pathological mechanisms involve pulmonary arterial endothelial cell dysfunction, abnormal proliferation of pulmonary arterial smooth muscle cell, and oxidative stress-driven vascular remodeling. Ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, is profoundly implicated in the pathological processes of various PH subtypes. This involvement occurs through the regulation of key pathways, including the system xc-/glutathione/glutathione peroxidase 4 axis, iron metabolism, and oxidases. However, the paradoxical coexistence of systemic iron deficiency and tissue iron deposition has been observed in PH. Therefore, a comprehensive understanding of ferroptosis in PH is crucial for successfully translating ferroptosis-targeted therapies from the laboratory to clinical practice. In this review, we first provide an overview of the current understanding of ferroptosis in PH, encompassing its molecular mechanisms, biological functions, regulatory pathways, and interactions with different PH subtypes. We also summarize the potential applications of ferroptosis biomarkers and therapeutic agents, including iron chelators, antioxidants, and lipid metabolism modulators, in the treatment of PH. Finally, moving beyond the limitations of single-agent targeting, we propose synergistic therapeutic strategies to offer novel perspectives for developing PH therapies.