Transcription factor EGR1 orchestrates ferroptosis to mitigate sepsis-induced myocardial injury by enhancing ferroportin expression.

OBJECTIVE: Myocardial injury is a devastating complication of sepsis and a leading cause of mortality in critically ill patients. This study aimed to investigate the role and underlying mechanisms of early growth response factor 1 (EGR1) in sepsis-induced myocardial injury (SIMI). MATERIAL AND METHODS: A rat model of SIMI was established using cecal ligation and puncture, and in vivo and in vitro experiments were conducted. In vivo, the myocardial tissue levels of cytokines, myocardial injury markers, apoptosis, and reactive oxygen species (ROS) were measured, along with the expression levels of EGR1, ferroportin (FPN), cystine/glutamate transporter ( xCT), and glutathione peroxidase 4 (GPX4). In vitro, H9c2 cardiomyoblast cell line ( H9c2) cardiomyocytes were transfected to overexpress or silence EGR1, and cell viability, oxidative stress, ferroptosis-related indicators, and mitochondrial membrane potential (ΔYm) were assessed. Transcriptome sequencing and dual-luciferase reporter gene assays were performed to analyze the mechanism of EGR1-mediated transcriptional regulation of FPN. RESULTS: Septic rats exhibited significant inflammation, myocardial injury, apoptosis, and oxidative stress. Transcriptome sequencing revealed that EGR1 expression was downregulated in the myocardium of septic rats and associated with the ferroptosis pathway. Dual-luciferase reporter gene assays confirmed that EGR1 is directly bound to and activates the FPN promoter. In vitro, EGR1 overexpression significantly promoted H9c2 cardiomyocyte viability, reduced malondialdehyde (MDA) and iron (II) ion (Fe(2+)) levels, increased glutathione (GSH) levels, upregulated the FPN/xCT/GPX4 axis, maintained ΔYm, and inhibited ROS production. Conversely, EGR1 knockdown exhibited opposite effects. In vivo, EGR1 overexpression effectively attenuated myocardial injury; improved myocardial histopathology; significantly increased EGR1, FPN, xCT, and GPX4 expression levels; significantly reduced serum Fe(2+) and MDA levels; increased GSH levels; and improved the survival rate of septic rats. CONCLUSION: This study provides a novel finding that EGR1 plays a pivotal protective role in myocardial injury through the direct transcriptional activation of FPN. Mechanistically, EGR1 alleviates SIMI by transcriptionally activating the FPN/xCT/GPX4 axis, which leads to the suppression of ferroptosis and oxidative stress and the preservation of mitochondrial function.