ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1621095
This article is part of the Research TopicUnraveling the Molecular Web of Inflammation and Fibrosis: Pathways, Immune Interactions, Epigenetics, and Therapeutic FrontiersView all 10 articles
Mechanistic Study of the hsa_circ_0074158 Binding EIF4A3 Impairing Sepsis-Induced Endothelial Barrier
Provisionally accepted
- 1Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- 2The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background: Sepsis remains a major clinical challenge, characterized by high rates of morbidity, mortality, and healthcare burden. Its complex pathogenesis involves multiple factors, with damage to the vascular endothelial barrier being a key component.Currently, there are no widely accepted biomarkers that demonstrate high sensitivity and specificity for sepsis, and treatment mainly focuses on supportive care without specific therapeutic targets. Recent research suggests that circRNA has potential as both a biomarker and a therapeutic target. In previous studies, the harmful role of hsa_circ_0074158 in worsening sepsis-induced endothelial barrier dysfunction was demonstrated through both in vitro and in vivo models, highlighting its potential as a biomarker and therapeutic target for sepsis.Methods: This study examined how hsa_circ_0074158 affects endothelial barrier function in sepsis. The role of hsa_circ_0074158 (circ_Ctnna1 in mice) in sepsis-related endothelial barrier dysfunction was studied using both in vitro and in vivo models.RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D experiments were used to show that circ_0074158 impacts endothelial barrier function in sepsis by reducing the stability of the host gene CTNNA1 (mRNA) after binding to EIF4A3.In both LPS-treated human umbilical vein endothelial cells (HUVECs) and cecal ligation and puncture (CLP) murine models, the overexpression of hsa_circ_0074158 (the mouse homolog of hsa_circ_0074158 is named circ_Ctnna1) significantly decreased CTNNA1 mRNA stability and increased endothelial hyperpermeability, while its knockdown restored barrier integrity. Mechanistically, RNA pull-down and RNA RIP assays demonstrated that hsa_circ_0074158 directly binds to the RNA-binding protein (RBP) EIF4A3, which decreases the stability of CTNNA1 (mRNA) and the production of α-catenin, subsequently impairing endothelial barrier function in sepsis. Rescue experiments showed that dual targeting of hsa_circ_0074158 and EIF4A3 restored endothelial barrier function. The dysregulation of the hsa_circ_0074158/EIF4A3 axis exacerbates sepsis-induced endothelial barrier dysfunction by destabilizing CTNNA1 mRNA, posing a critical medical challenge due to its complex pathophysiology.This study provides new insights into the molecular mechanisms of sepsis and suggests potential therapeutic targets for its treatment. Further research is needed to explore the clinical application of these findings.
Keywords: Sepsis, hsa_circ_0074158, EIF4A3, RNA-Binding Protein, Endothelial barrier function
Received: 30 Apr 2025; Accepted: 31 Aug 2025.
Copyright: © 2025 Liao, Li, Zhang, Peng and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Haiyan Liao, Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.