Esketamine alleviated cardiomyocyte ferroptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R) via cyclic GMP-AMP synthase interactor.

In patients undergoing total knee arthroplasty, tourniquet use causes limb ischemia-reperfusion injury that releases inflammatory cytokines and reactive oxygen species, leading to myocardial damage. In a randomized trial with 23 patients, those receiving 0.5 mg/kg esketamine alongside conventional anesthesia showed higher levels of the antioxidants glutathione peroxidase and glutathione, and lower levels of inflammatory markers IL-6 and TNF-α, oxidative stress marker malondialdehyde, iron (Fe2+), and cardiac injury markers creatine kinase, CK-MB, and lactate dehydrogenase, compared to controls. In cell experiments, esketamine reduced oxygen-glucose deprivation/reperfusion-induced increases in malondialdehyde, Fe2+, and reactive oxygen species, and prevented decreases in glutathione peroxidase, glutathione, GPX4, and FTH1; these effects were reversed by overexpressing STING. Esketamine appears to alleviate cardiomyocyte ferroptosis via STING, which may explain its protective effect against myocardial injury from tourniquet-induced ischemia-reperfusion.

Study at a glance

Abstract

The use of tourniquets (TQ) during the total knee arthroplasty (TKA) induced ischemia-reperfusion (I/R) injury in the limb, resulting in the release of inflammatory cytokines and reactive oxygen species (ROS), therefore leading to myocardial damage. This study aimed to investigate the effects and molecular mechanism of Esketamine on myocardial injury (MI) caused by TQ-induced I/R injury. A randomized numerical table method was used to divide 23 patients into the C group (11 cases, ACB + conventional anesthesia) and M group (12 cases, ACB + conventional anesthesia + 0.5 mg/kg Esketamine). The levels of lactate dehydrogenase (LDH), Malondialdehyde (MDA), Fe2+, Glutathione Peroxidase (GSH-Px), glutathione (GSH), IL-6, TNF-α, Creatine Kinase (CK) and CreatineKinase-MB (CKMB) were determined by reagent kits. The expression of CGAMP interaction factor (STING), Glutathione Peroxidase 4 (GPX4), and Ferritin Heavy Chain 1 (FTH1) was examined by Western blot. The ROS level was tested by flow cytometry. The expression of STING was validated by immunofluorescence. Compared with the C group, the levels of GSH-Px and GSH were increased while the levels of IL-6, TNF-α, MDA, Fe2+, CK, CKMB, and LDH were decreased in the M group. Furthermore, esketamine relieved the OGD/R-induced increase of MDA, Fe2+, and ROS and the decrease of GSH-Px, GSH, GPX4, and FTH1, which were reversed by STING overexpression. Esketamine alleviated cardiomyocyte ferroptosis via STING, which might be the molecular mechanism of Esketamine to ameliorate the MI caused by TQ-induced I/R injury. The online version contains supplementary material available at 10.1007/s10616-025-00723-9.