Ferroptosis Promotes Pulmonary Hypertension

The accumulation of iron-dependent lipid peroxides induces ferroptosis, a nonapoptotic form of cell death that integrates metabolic derangements with oxidative stress(1). Multiple organelles regulate ferroptosis, but the mitochondria may be the most important organelle as mitochondria both initiate and propagate ferroptosis(1). Altered ferroptosis homeostasis is linked to multiple diseases including cancer, sepsis, cardiovascular diseases, and aging. In the cardiovascular realm, ferroptosis underlies mitochondrial dysfunction and impaired cardiac contractility due to both ischemic and non-ischemic insults(1). Additionally, ferroptosis induces endothelial cell dysfunction and accelerates atherosclerosis development in mice(2). At present, the role of ferroptosis in the pulmonary vasculature is relatively unexplored. However, pulmonary arterial endothelial cell dysfunction, characterized by disrupted mitochondrial function and impaired iron and lipid metabolism(4), contributes to pulmonary hypertension (PH) pathobiology. These molecular phenotypes provide a plausible link between pulmonary vascular disease and ferroptosis. Additionally, ferroptosis inhibition, starting before administration of monocrotaline (MCT), blunts PH severity in rats(3), but the preventative approach used in this study may limit its translatability. Here, we employed a drug intervention in translational rodent studies, quantitative lung proteomics, and a human genetic association study to evaluate how ferroptosis modulates PH severity.