Esketamine induces ferroptosis and suppresses immune evasion in lung adenocarcinoma cells via the hsa_circ_0022392/miR-548b-3p/MAP7 axis

Abstract

Although Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for anesthesia and analgesia and has shown anticancer activity, its effects on lung adenocarcinoma remain unclear. Circular RNAs have been implicated in the development and progression of lung adenocarcinoma. Therefore, this study aims to elucidate whether esketamine can influence lung adenocarcinoma progression by interfering with the circular RNA hsa_circ_0022392. Expression levels of hsa_circ_0022392, miR-548b-3p, and microtubule-associated protein 7 (MAP7), as well as transfection efficiency, were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Cell viability was assessed using the Cell Counting Kit-8 assay. 5-ethynyl-2’-deoxyuridine (EdU) assay was employed to examine cell proliferation. Transwell assays were employed for analyzing cell migration and invasion capabilities. Intracellular Fe²⁺ levels, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) were measured using commercial kits. Lactate dehydrogenase (LDH) release assays were adopted to evaluate CD8⁺ T-cell cytotoxicity. Cytokine levels were measured via ELISA. Bioinformatics analysis combined with RNA immunoprecipitation and dual-luciferase reporter assays were employed to confirm the target relationship between miR-548b-3p and hsa_circ_0022392 or MAP7. Esketamine significantly inhibited proliferation, migration, and invasion (all P  < 0.05), induced ferroptosis ( P  < 0.05), and suppressed immune evasion ( P  < 0.05). Notably, hsa_circ_0022392 expression was upregulated in lung adenocarcinoma tissues and cell lines ( P  < 0.01), and esketamine downregulated its levels ( P  < 0.05). Overexpressed hsa_circ_0022392 notably reversed esketamine’s inhibitory effect on lung adenocarcinoma cell progression ( P  < 0.05). Further studies revealed that hsa_circ_0022392 targeted and bound to miR-548b-3p, thereby upregulating MAP7 expression ( P  < 0.05). Interfering with this signaling axis effectively weakened the inhibitory effect of esketamine on lung adenocarcinoma progression ( P  < 0.05). In summary, esketamine promotes ferroptosis in lung adenocarcinoma cells through regulating the hsa_circ_0022392/miR-548b-3p/MAP7 axis and inhibits immune evasion, providing novel molecular targets and therapeutic strategies for the diagnosis and treatment of lung adenocarcinoma.