GPX4 is a key ferroptosis biomarker and correlated with immune cell populations and immune checkpoints in childhood sepsis

Abstract

Sepsis is the uncontrolled reaction of the body to infection-induced inflammation, which results in life-threatening multiple-organ dysfunction (MODS). Although the research on sepsis has advanced significantly in recent years, its pathophysiology remains entirely unknown. Ferroptosis is a new-fashioned type of programmed cell death that may have an impact on sepsis development. However, the precise mechanism still needs to be explored. In this paper, Four pediatric sepsis datasets [training datasets (GSE26378 and GSE26440) and validation datasets (GSE11755 and GSE11281)] were chosen through the GEO (Gene Expression Omnibus) database, and 63 differentially expressions of ferroptosis-relation-genes (DE-FRGs) were eventually discovered using bioinformatics investigation. Functional annotation was performed using GO and KEGG pathway enrichment analysis. Then, four Core-FRGs (FTH1, GPX4, ACSL1, and ACSL6) were extracted after the construction of the protein–protein interaction (PPI) network and the research of the MCODE module. Consequently, Hub-FRG (GPX4) was found using the validation datasets, and correlation exploration of immunity populations (neutrophils, r = − 0.52; CD8 T-cells, r = 0.43) and immunity checkpoints (CD274, r = − 0.42) was implemented. The usefulness of GPX4 as a marker in sepsis was assessed in a mouse model of sepsis. The findings demonstrate that GPX4 is a crucial biomarker and a new latent immunotherapy target for the prediction and therapy of pediatric sepsis.

Machine learning reveals ferroptosis features and a novel ferroptosis classifier in patients with sepsis

“…Ferroptosis plays an active role in regulating immune function in an inflammatory environment 38,39 . In recent years, new views believe that ferroptosis has broad prospects in the occurrence, development, and prevention of sepsis 11,12 . Therefore, the utility of FRGs as potential biomarkers was explored in this study.…”

“… 38 , 39 In recent years, new views believe that ferroptosis has broad prospects in the occurrence, development, and prevention of sepsis. 11 , 12 Therefore, the utility of FRGs as potential biomarkers was explored in this study. The analysis results of MEGENA and DFGs were combined to find the characteristic ferroptosis genes in the peripheral blood of septic patients.…”

“… 8 In recent years, ferroptosis has also been shown to be involved in various diseases and pathological processes. 9 , 10 Recently, it has been reported that ferroptosis regulated by Glutathione Peroxidase 4 (GPX4) may be a new pathophysiological mechanism of sepsis, 11 that inhibits ferroptosis from playing a protective role in septic lung injury. 12 Thus, exploring the contribution of ferroptosis in sepsis can be potentially useful.…”

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials

“…GPX4, a key enzyme in ferroptosis [59,60], plays a crucial role in averting irondependent toxic lipid ROS formation by converting lipid hydroperoxides to lipid alcohols. The inhibition of GPX4 function induces lipid peroxidation, eventually leading to ferroptosis [61].…”

GDF15 Improves Lipopolysaccharide-Induced Myocardial Dysfunction By Inhibiting Cardiomyocyte Ferroptosis Via The SOCS1/GPX4 Signaling Pathway Regulation

“…Maintenance of iron homeostasis is essential for normal cardiac function. Ferroptosis regulates the pathogenesis and progression of many cardiovascular diseases [15,16] and exacerbates fatal sepsis [17]. Qu et al showed that glutathione peroxidase 4 (GPX4), a ferroptosis marker, is associated with immune cell populations in sepsis [18].…”