Melatonin mitigates the lipopolysaccharide-induced myocardial injury in rats by blocking the p53/xCT pathway-mediated ferroptosis.

This article examined the therapeutic effect of melatonin (MT) on the lipopolysaccharide (LPS)-induced myocardial injury, and the mechanisms involved. Septic rat model was constructed by exposing to lipopolysaccharide (LPS), and treated by MT, Ferrostatin-1 (Fer-1) and Erastin (Era). Hematoxylin-eosin staining was executed to appraise myocardial injury. H9c2 cells that exposed to LPS to induce in vitro sepsis cell model were treated by MT. p53 overexpression vectors were transfected into H9c2 cells. Inflammation- and ferroptosis-related indicators were examined by enzyme-linked immunosorbent assay. Expression of p53, xCT and GPX4 was scrutinized by quantitative real-time polymerase chain reaction and Western blot. MT relieved myocardial injury in septic rats. It decreased IL-6 and TNF-α, elevated GPX4 and GSH, and reduced MDA and Fe in myocardial tissues of septic rats. LPS induced p53 elevation and xCT reduction in rats' myocardial tissues. Nevertheless, MT treatment declined p53 and increased xCT in myocardial tissues of septic rats. Interestingly, the relieving effect of MT on myocardial injury in septic rats was enhanced by Fer-1, but reversed by Era. The LPS-induced H9c2 cell damage was relieved by MT treatment. Besides, MT decreased LDH, IL-6 and TNF-α, elevated xCT, GPX4 and GSH, and reduced MDA and Fe in the LPS-induced H9c2 cells. Conversely, these influences of MT on the LPS-induced H9c2 cells were reversed by p53 overexpression. MT is proposed to be a promising agent for treating the LPS-induced myocardial injury, as it relieves myocardial injury by hindering the p53/xCT-mediated ferroptosis in the LPS-induced septic rats.