xCT/Slc7a11 promotes pulmonary arterial hypertension by disrupting AMPKα suppression of mTOR activation.

While mTOR plays a key role in the development of pulmonary arterial hypertension (PAH), its suppressor, AMPKα, acts as an inhibitor. Although mTOR-driven transcriptional upregulation of the plasma membrane exchanger and amino acid transporter xCT, encoded by the Slc7a11 gene, is critical for cell proliferation and tumorigenesis, the involvement of xCT in PAH remains unexplored. In this study, we found that xCT expression was elevated in hypoxia-treated human pulmonary arterial endothelial cells (HPAECs) and the lungs of hypoxia-exposed mice and Sugen5416/hypoxia (SuHx)-induced PAH mice. Knockout of xCT prevented the development of PAH and right heart failure in SuHx-conditioned mice. The xCT inhibitor sulfasalazine prevented and reversed SuHx-induced PAH in mice. Deleting and inhibiting xCT activated AMPKα and inactivated mTOR in mouse lungs with PAH and in HPAECs. Sulfasalazine suppressed mTOR through activation of AMPKα in HPAECs. The mTOR inhibitor rapamycin reduced xCT expression, activated AMPKα, and suppressed mTOR in HPAECs. These findings suggest that xCT promotes the development of PAH, likely through suppression of AMPKα and activation of mTOR. Blockage of xCT and mTOR or activation of AMPKα by existing drugs such as sulfasalazine, sirolimus, and metformin may offer readily therapeutic strategies for PAH.