xCT/SLC7A11-mTOR axis promotes vascular remodeling in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a fatal vascular disorder characterized by excessive endothelial proliferation and dysregulated angiogenesis, leading to progressive vascular remodeling. However, the molecular mechanisms driving these endothelial alterations remain incompletely understood. In this study, we identify the cystine/glutamate antiporter xCT (SLC7A11) as a key regulator of endothelial function in PAH. Transcriptomic analysis of pulmonary endothelial cells from PAH mice revealed significant upregulation of xCT expression. In vitro, hypoxia robustly induced xCT expression in human pulmonary artery endothelial cells. Overexpression of xCT promoted endothelial cell proliferation and angiogenic capacity, while pharmacological inhibition of xCT with sulfasalazine (SASP) effectively suppressed these processes in a dose-dependent manner. Further analysis demonstrated that xCT-driven endothelial activation is dependent on mTOR signaling pathway, as mTOR inhibition reversed the functional effects of xCT overexpression. These findings reveal a novel xCT-mTOR regulatory axis that governs vascular remodeling in PAH. Targeting xCT may offer a new therapeutic avenue to mitigate disease.