METTL14 Inhibits Human Lung Microvascular Endothelial Cell From Ferroptosis in Septic Lung Injury by Regulating N ⁶ ‐Methyladenosine‐Modified ACSL4 Level

Background N 6 ‐methyladenosine (m 6 A) RNA modification is involved in numerous physiological and pathological processes. However, the specific role of m 6 A modification in septic lung injury remains unknown. Methods Here, caecal ligation and puncture (CLP) operation was performed to induce septic lung injury in mice, and the establishment of the animal model was verified by haematoxylin and eosin (H&E) staining of lung tissues. The mRNA levels of m 6 A writers in blood samples from septic lung injury model mice were assessed. The intracellular concentrations of Fe 2+ , glutathione (GSH), malondialdehyde (MDA) and reactive oxygen species (ROS) were quantified to evaluate ferroptosis in HULEC‐5a cells. In addition, the mitochondrial ultrastructure of HULEC‐5a cells was observed by transmission electron microscopy (TEM). The MeRIP assay was performed to detect the m 6 A modification of ACSL4 mRNA. The binding of ACSL4 to METTL14 was verified using RIP and dual luciferase gene reporter assays. Results In this study, METTL14 was identified as aberrantly downregulated in septic lung injury models. Highly expressed METTL14 significantly protected HULEC‐5a cells from LPS‐induced ferroptosis. Meanwhile, METTL14 increased m 6 A methylation of ACSL4 mRNA and inhibited ACSL4 mRNA levels by suppressing its stability. Mechanistically, METTL14 mediates the m 6 A modification of ACSL4 in a manner dependent on the m 6 A reader protein YTHDC1. These findings support a role for METTL14‐mediated modification of ACSL4 and the subsequent suppression of ferroptosis in the pathogenesis of septic lung injury. Conclusions Our data support that ferroptosis‐induced damage is a pathogenic event during septic lung injury and that targeting METTL14 may have therapeutic potential for the treatment of septic lung injury.