Esketamine alleviates ferroptosis-mediated acute lung injury by modulating the HIF-1α/HO-1 pathway

  • Int Immunopharmacol. 2024 Dec 5;142(Pt A):113065. doi: 10.1016/j.intimp.2024.113065.
Jinye Shi  1 ,  Shuang Song  2 ,  Yajie Wang  3 ,  Kaixuan Wu  1 ,  Gui Liang  1 ,  Aizhong Wang  4 ,  Xiaotao Xu  5
Affiliations
  • 1. Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China.
  • 2. Department of Respiratory Medicine, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China.
  • 3. Reproductive Medicine Center, General Hospital of Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia, China.
  • 4. Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China. Electronic address: [email protected].
  • 5. Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China. Electronic address: [email protected].
PMID: 39243557 DOI: 10.1016/j.intimp.2024.113065
Abstract

Background: Alveolar epithelial cell (AEC) Ferroptosis contributes to the progression of acute lung injury (ALI). Esketamine (ESK) is a new clinical sedative, anesthetic, and analgesic drug that has attracted substantial attention in mental health research because of its antidepressant effects. However, the effects of ESK on ferroptosis-mediated ALI remain unclear.

Objective: This study aimed to explore the protective effect of ESK on AEC Ferroptosis in ALI and its potential molecular mechanism in vivo and in vitro.

Methods: The antiferroptotic and anti-inflammatory effects of ESK were assessed in a mouse model of lipopolysaccharide (LPS)-induced ALI. In vitro, the epithelial cell lines MLE-12 and A549 were used to examine the underlying mechanism by which ESK regulates inflammation and Ferroptosis.

Results: ESK protected mice against LPS-induced ALI, significantly attenuated pathological changes in the lungs and decreased inflammation and Ferroptosis. In vitro, ESK inhibited LPS-induced inflammation and Ferroptosis in MLE-12 and A549 cells. Moreover, Ferroptosis mediated inflammation in LPS-induced ALI in vivo and in vitro, and ESK decreased the LPS-induced inflammatory response by suppressing Ferroptosis. ESK promoted the HIF-1α/HO-1 pathway in LPS-treated AECs and in the lung tissues of mice with LPS-induced ALI. Moreover, pretreatment with ESK and the HIF-1α stabilizer dimethyloxaloylglycine (DMOG) substantially attenuated lung injury and prevented changes in ferroptosis-related biochemical indicators, including glutathione (GSH) depletion, malondialdehyde (MDA) production and Glutathione Peroxidase 4 (GPX4) downregulation, in untreated LPS-induced mice but not in LPS-induced mice treated with the HO-1 inhibitor zinc protoporphyrin (ZNPP). Similar effects were observed in vitro in HO-1 siRNA-transfected A549 cells after LPS incubation but not in control siRNA-transfected cells.

Conclusion: ESK can inhibit ferroptosis-mediated lipid peroxidation by increasing the expression of HIF-1α/HO-1 pathway, highlighting the potential of ESK to treat LPS-induced ALI.

Keywords
Acute lung injury; Alveolar epithelial cell; Esketamine; Ferroptosis.
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