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

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.