Targeting Glutamate transport: A breakthrough in mitigating sepsis lung injury

  • Free Radic Biol Med. 2025 Aug 1:235:190-199. doi: 10.1016/j.freeradbiomed.2025.04.043.
Yu-Jia Qiu  1 ,  Fan Zhan  2 ,  Hai-Peng Cheng  3 ,  Min Shao  1 ,  Xiao-Hong Li  2 ,  Xing-Wen Bao  1 ,  Xin-Yue Liang  1 ,  Qian Zeng  4 ,  Wei Liu  4 ,  Si-Yuan Tang  4 ,  Yang Han  1 ,  Dan-Dan Feng  1 ,  Shao-Jie Yue  5 ,  Yan Zhou  6 ,  Zi-Qiang Luo  7
Affiliations
  • 1. Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China.
  • 2. The First Affiliated Hospital, University of South China, Hengyang, Hunan, 410000, China.
  • 3. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
  • 4. Xiangya Nursing School, Central South University, Changsha, Hunan, 410000, China.
  • 5. Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China.
  • 6. Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China. Electronic address: [email protected].
  • 7. Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, China. Electronic address: [email protected].
PMID: 40294854 DOI: 10.1016/j.freeradbiomed.2025.04.043
Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) can result from various factors, including sepsis, one of the high-risk causes of ALI/ARDS. Recent research emphasizes the role of Glutamate metabolism in ALI/ARDS. Our study found a strong correlation between the difference in serological Glutamate levels of arterial vs venous blood and the progression of lung injury. High arterial - venous (A-V) Glutamate discrepancies were significantly associated with severity in ALI/ARDS patients. Additionally, the subunit of Glutamate transporter system XC- was notably elevated in mouse lungs affected by sepsis and LPS-induced macrophages. Pharmacological inhibition of system XC- or knocking down xCT worsened sepsis-related lung injury in mice. We also showed that xCT in macrophages is essential for activating system XC- for Glutamate transport, offering protection against sepsis-related ALI. Our findings highlight the therapeutic potential of Glutamate transport in mitigating lung injury and provide a promising approach for predicting ALI/ARDS prognosis.

Keywords
Acute lung injury; Glutamate; Macrophages; Sepsis; System X(C)(−); xCT.
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