2. Academic Validation
  3. xCT/Slc7a11 promotes pulmonary arterial hypertension by disrupting AMPKα suppression of mTOR activation

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

  • Biochem Pharmacol. 2025 Jun:236:116897. doi: 10.1016/j.bcp.2025.116897.
Yan Meng 1,  Cuiting Zheng 2,  Xiyu Zhang 3,  Zhenqiang Gao 3,  Hongyu Chen 4,  Xianmei Qi 5,  Kai Li 4,  Fangming Liu 4,  Weiwei Deng 4,  Yuting Wu 4,  Jie Liu 5,  Chen Chen 6,  Chen Wang 4,  Heng Zhao 7,  Hongbing Zhang 8
Affiliations

Affiliations

  • 1 Department of Pathology, Capital Medical University, Beijing, China. Electronic address: yanmeng_my@ccmu.edu.cn.
  • 2 Department of Pathology, Capital Medical University, Beijing, China; State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 3 Department of Pathology, Capital Medical University, Beijing, China.
  • 4 State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 5 Department of Immunology, Capital Medical University, Beijing, China.
  • 6 Beijing Luhe Hospital, Capital Medical University, Beijing, China.
  • 7 Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Joint Innovation Center for Brain Disorders, Capital Medical University, Beijing, China. Electronic address: hengzhao@ccmu.edu.cn.
  • 8 State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. Electronic address: hbzhang@ibms.pumc.edu.cn.
PMID: 40147801 DOI: 10.1016/j.bcp.2025.116897
Abstract

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.

Keywords

AMPKα; Pulmonary arterial hypertension; Sulfasalazine; mTOR; xCT.

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